CN114671825B - 一种含硒芳基的手性4h-3,1-苯并噁嗪类化合物的合成方法 - Google Patents
一种含硒芳基的手性4h-3,1-苯并噁嗪类化合物的合成方法 Download PDFInfo
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/16—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with only hydrogen or carbon atoms directly attached in positions 2 and 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明公开了一种含硒芳基的手性4H‑3,1‑苯并噁嗪类化合物的合成方法;属于有机合成领域;该合成方法具体包括以下步骤:室温下,将1,1‑二取代烯烃、硒芳基试剂、催化剂和溶剂加入反应管中,在低温条件下进行反应,加入酸,于氩气氛围中进行反应,后经减压蒸馏、柱色谱提纯,制得含硒芳基的手性4H‑3,1‑苯并噁嗪类化合物。本发明的合成方法能够得到较高收率与对映选择性的手性4H‑3,1‑苯并噁嗪类化合物,且该方法操作简单,条件温和,可以克级制备,反应底物范围广,适用性高。
Description
技术领域
本发明属于有机化学合成技术领域,具体涉及一种含硒芳基的手性4H-3,1-苯并噁嗪类化合物的合成方法。
背景技术
有机硒化物不仅广泛存在于药物分子、天然产物等生物活性化合物中,在石油化工产业中也存在广泛应用,而且作为手性催化剂/配体在不对称催化以及材料科学中起着重要作用,同时在合成化学中也是非常重要的中间体。如何高效的构建C-Se键一直都是现代有机化学的研究热点及难点,吸引了无数的科研工作者为之奋斗。由于有机硒化物在生物、医药及各种手性配体中的广泛应用,合成化学家们研究出了众多构建C-Se键的方法,主要包括加成和取代反应。其中烯烃的催化不对称亲电硒基化是制备手性有机硒化合物的最直接和有效的策略之一,近来引起了越来越多的关注。
4H-3,1-苯并噁嗪结构是一种含N,O-的六元杂环,广泛存在于各种生物活性分子中,如药物和农药。然而,尽管大量4H-3,1-苯并噁嗪衍生物具有良好的生物活性,但它们的对映选择性合成方法非常有限。目前,仅报道了三个催化不对称合成4H-3,1-苯并噁嗪衍生物的例子。Toste等相关人员在手性阴离子相转移催化条件下,通过邻苯胺基苯乙烯的对映选择性卤环化,开发了一种不对称合成卤代4H-3,1-苯并噁嗪的方法(J.Am.Chem.Soc.2012,134,12928-12931)。Feringa等相关人员报道了通过Ir催化的不对称分子内烯丙基酰胺化催化对映选择性合成4H-3,1-苯并噁嗪衍生物,然而手性中心的范围仅限于单乙烯基取代(Chem.Sci.2014,5,4216-4220)。Deng等相关人员开发了一种金鸡纳碱衍生物催化的不对称合成氯代4H-3,1-苯并噁嗪的方法(J.Org.Chem.2020,85,1882-1893)。因此,开发具有广泛底物范围和多种取代基的4H-3,1-苯并恶嗪对映选择性合成的新策略仍有需求。
发明内容
本发明的目的在于提供一种具有较高收率与对映选择性的手性4H-3,1-苯并噁嗪类化合物的合成方法,且该方法操作简单,条件温和,可以克级制备,反应底物范围广,适用性高。
本发明为实现上述目的所采取的技术方案为:
一种含硒芳基的手性4H-3,1-苯并噁嗪类化合物,其化学结构式如下所示:
R1选自R1选自氢、C1~6烷基、C1~6烷氧基、苯基、取代苯基、噻吩基或者2-萘基;
R2选自环己基、苯基或者取代苯基;
R3选自氢、C1~6烷基、C1~6烷氧基或者苯基;
R4选自氢、C1~6烷基或者C1~6烷氧基。
进一步地,于一实施方式中,R1选自甲基、苯基、对氟苯基、对叔丁基苯基、对甲氧基苯基、噻吩基或者2-萘基。
进一步地,于一实施方式中,R2选自苯基、环己基、对氟苯基、对溴苯基、间溴苯基、间甲氧基苯基或者对氯苯基。
进一步地,于一实施方式中,R3选自H或者苯基。
进一步地,于一实施方式中,R4选自甲基、异丙基或者叔丁基。
本发明还公开了一种含硒芳基的手性4H-3,1-苯并噁嗪类化合物的合成方法,包括:将1,1-二取代烯烃与硒芳基试剂,在催化剂、酸以及溶剂的共同作用下,生成含硒芳基的手性4H-3,1-苯并噁嗪类化合物。
进一步地,于一实施方式中,一种含硒芳基的手性4H-3,1-苯并噁嗪类化合物的合成方法,具体包括以下步骤:
室温下,将1,1-二取代烯烃、硒芳基试剂、催化剂和溶剂加入反应管中,在低温条件下进行反应,加入酸,于氩气氛围中进行反应,后经减压蒸馏、柱色谱提纯,制得含硒芳基的手性4H-3,1-苯并噁嗪类化合物。
本发明采用1,1-二取代烯烃与硒芳基试剂为原料,在手性路易斯碱和非手性路易斯酸的共催化体系下,合成了收率高、对映选择性高的含硒芳基的手性4H-3,1-苯并噁嗪类化合物;该合成方法操作简单,条件温和,可以克级制备,且反应底物范围广,适用性高;除此之外,得到的含硒芳基的手性4H-3,1-苯并噁嗪类化合物可以进一步衍生化,进而得到新型的手性4H-3,1-苯并噁嗪类化合物。
进一步地,于一实施方式中,酸为三氟化硼四氢呋喃或三氟化硼乙醚溶液;所述溶剂为氘代氯仿、甲苯、二甲苯、异丙醇中的至少一种。
进一步地,于一实施方式中,1,1-二取代烯烃与硒芳基试剂的摩尔比为1:0.8~2。
进一步地,于一实施方式中,1,1-二取代烯烃与催化剂的摩尔比为1:0.05~0.15。
进一步地,于一实施方式中,1,1-二取代烯烃与酸的摩尔比为1:0.5~1.5。
进一步地,于一实施方式中,低温为-25~-5℃,反应时间为72~96h。
进一步地,于一实施方式中,反应体系后处理方式为:反应结束后反应体系经过减压蒸馏除去溶剂,随后进行柱层析,以石油醚/乙酸乙酯体积比30~50:1洗脱,收集目标产物的洗脱液后进行减压蒸馏的目标产物。
进一步地,于一实施方式中,1,1-二取代烯烃的化学结构如式(I)所示;所述硒芳基试剂的化学结构如式(II)所示;所述催化剂的化学结构如式(III)所示;所述含硒芳基的手性4H-3,1-苯并噁嗪类化合物的化学结构如式(IV)所示;
其中,R1选自R1选自氢、C1~6烷基、C1~6烷氧基、苯基、取代苯基、噻吩基或者2-萘基;
R2选自环己基、苯基或者取代苯基;
R3选自氢、C1~6烷基、C1~6烷氧基或者苯基;
R4选自氢、C1~6烷基或者C1~6烷氧基。
本发明还公开了一种含硒芳基的手性4H-3,1-苯并噁嗪类化合物的合成方法,其合成路线如下:
其中,R1选自氢、C1-6烷基、C1-6烷氧基、苯基、对氟苯基、对叔丁基苯基、对甲氧基苯基、噻吩基或者2-萘基;
R2选自苯基、苄基、环己基、对氟苯基、对溴苯基、间溴苯基、间甲氧基苯基或者对氯苯基;
R3选自氢、C1~6烷基、C1~6烷氧基或者苯基;
R4选自氢、甲基、乙基、丙基、异丙基、正丁基、异丁基或者叔丁基。
进一步地,于一实施方式中,含硒芳基的手性4H-3,1-苯并噁嗪类化合物的收率>50%,ee值≥90%。
本发明还公开了一种含硒芳基的手性4H-3,1-苯并噁嗪类化合物在催化不对称反应中的用途。
与现有技术相比,本发明具有以下特点:
1)本发明方法操作简单,条件温和,可以克级制备,且具有收率高、对映选择性高等优点。
2)本发明方法采用手性路易斯碱和非手性路易斯酸的共催化体系,反应底物范围广,适用性高。
3)本发明方法得到的含硒芳基的手性4H-3,1-苯并噁嗪类化合物可以进一步衍生化,进而得到新型的手性4H-3,1-苯并噁嗪类化合物。
附图说明
图1为化合物1的1H核磁共振光谱;
图2为化合物1的13C核磁共振光谱;
图3为化合物2的1H核磁共振光谱;
图4为化合物2的13C核磁共振光谱;
图5为化合物2的19F核磁共振光谱;
图6为化合物3的1H核磁共振光谱;
图7为化合物3的13C核磁共振光谱;
图8为化合物4的1H核磁共振光谱;
图9为化合物4的13C核磁共振光谱;
图10为化合物5的1H核磁共振光谱;
图11为化合物5的13C核磁共振光谱;
图12为化合物6的1H核磁共振光谱;
图13为化合物6的13C核磁共振光谱;
图14为化合物7的1H核磁共振光谱;
图15为化合物7的13C核磁共振光谱;
图16为化合物7的19F核磁共振光谱;
图17为化合物8的1H核磁共振光谱;
图18为化合物8的13C核磁共振光谱;
图19为化合物9的1H核磁共振光谱;
图20为化合物9的13C核磁共振光谱;
图21为化合物10的1H核磁共振光谱;
图22为化合物10的13C核磁共振光谱;
图23为化合物11的1H核磁共振光谱;
图24为化合物11的13C核磁共振光谱;
图25为化合物12的1H核磁共振光谱;
图26为化合物12的13C核磁共振光谱;
图27为化合物13的1H核磁共振光谱;
图28为化合物13的13C核磁共振光谱;
图29为化合物14的1H核磁共振光谱;
图30为化合物14的13C核磁共振光谱;
图31为化合物15的1H核磁共振光谱;
图32为化合物15的13C核磁共振光谱;
图33为化合物16的1H核磁共振光谱;
图34为化合物16的13C核磁共振光谱;
图35为化合物16的19F核磁共振光谱;
图36为化合物17的1H核磁共振光谱;
图37为化合物17的13C核磁共振光谱;
图38为化合物18的1H核磁共振光谱;
图39为化合物18的13C核磁共振光谱。
具体实施方式
下面通过实施例对本发明做进一步阐述,其目的仅在于更好理解本发明的内容。因此,本专利的保护范围并不限于这些实施例。
需要说明的是,本发明中使用的术语“烷基”是指具有规定数目碳原子的完全饱和的支链或非支链烃链。例如,C1~6烷基是指具有1~6个碳原子的烷基。
需要说明的是,本发明中使用的术语“烷氧基”是指通过氧桥连接的任何烷基部分(即-O-C1~3烷基基团,其中C1~3烷基如本文所定义)。此类基团的示例包括但不限于甲氧基、乙氧基和丙氧基。例如,C1~6烷氧基是指具有1至6个碳原子的烷氧基。
需要说明的是,本发明中使用的术语“光学异构体”或“立体异构体”是指本发明指定化合物可能存在的任何各种立体异构构型,包括几何异构体。应当理解,取代基可以与碳原子的手性中心连接。术语“手性”是指与其镜像分子对具有非重叠性特征的分子,而术语“非手性”是指与其镜像分子对能够重叠的分子。因此,本发明包括化合物的对映异构体、非对映异构体或外消旋体。“对映异构体”是彼此镜像不重叠的一对立体异构体。
需要说明的是,本发明的实施方式中,化合物的氢核磁共振谱(1H NMR、13C NMR和19F NMR)由Bruker AVANCE III HD 400测定,溶剂为氘代氯仿。化学位移(δ)以ppm为单位引用,以四甲基硅烷作为内标,多重性:s=单重态,d=双重态,t=三重态,q=四重态,m=多重态。高分辨率质谱分析(HRMS)数据是通过ESI技术和傅里叶变换离子回旋加速器(SolariX 7.0T)的Q-TOF质谱测得。采用Daicel Chiralpak AS-H、Daicel Chiralpak AD、DaicelChiralpak AD-H、Daicel Chiralpak IB、Chiralcel OD-H通过高效液相色谱(HPLC)分析测定产品的对映体过量(ee)。
需要说明的是,本发明结构式(I)所示化合物的合成路径如下:
其中,R1选自甲基、苯基、对氟苯基、对叔丁基苯基、对甲氧基苯基、噻吩基或者2-萘基;R2选自苯基、环己基、对氟苯基、对溴苯基、间溴苯基、间甲氧基苯基或者对氯苯基;R3选自H或者苯基;R4选自甲基、异丙基或者叔丁基。
需要说明的是,本发明结构式(I)所示化合物的制备方法如下:
在封管中加入相应的苯胺(1.0当量),炔烃(1.0当量)和蒙脱土K10(100mg/mmol),140℃下反应12h。反应体系用二氯甲烷溶解过滤后,减压蒸馏除去溶剂后,直接柱层析得到产物2-(1-苯基乙烯基)苯胺,该产物未经过进一步纯化直接投下一步;
将2-(1-苯基乙烯基)苯胺(1.0当量)溶于二氯甲烷并加入三乙胺(1.5当量),于室温下缓慢滴加相应的酰氯(1.2当量),室温下反应6h后,减压蒸馏除去溶剂,直接柱层析得到原料(I)。
本发明中结构式(I)所示化合物选自以下其中的一种:
其中,Ph为苯基;t-Bu为叔丁基;i-Pr为异丙基;Ar为2-硝基苯基。
需要说明的是,本发明结构式(I)所示化合物的表征数据如下所示:
(1)化合物(I-1)N-(3-异丙基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.70-7.58(m,3H),7.52-7.35(m,7H),7.31-7.19(m,7H),6.99(s,1H),5.69(s,1H),5.43(s,1H),3.15(hept,J=6.9Hz,1H),1.28(d,J=6.8Hz,6H);13C NMR(101MHz,Chloroform-d)δ166.39,148.00,147.49,141.04,141.02,140.59,140.36,134.26,131.58,131.08,128.92,128.80,128.42,128.03,127.56,127.41,127.28,127.12,126.49,124.99,116.97,28.92,23.83;HRMS(ESI)m/z:[M+Na]+calcd forC30H27NONa 440.1990;found440.1984。
(2)化合物(I-2)4-氟-N-(3-异丙基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.69-7.58(m,3H),7.53-7.43(m,3H),7.40-7.31(m,3H),7.25(s,5H),6.98(t,J=8.6Hz,2H),6.89(s,1H),5.70(s,1H),5.43(s,1H),3.12(hept,J=6.9Hz,1H),1.28(d,J=6.9Hz,6H);13C NMR(101MHz,Chloroform-d)δ165.35,164.85(d,J=252.0Hz),148.01,147.44,141.18,140.96,140.60,140.27,130.89,130.38(d,J=3.2Hz),129.48(d,J=8.9Hz),128.95,128.85,128.08,127.62,127.42,127.34,126.46,125.07,117.16,115.44(d,J=21.9Hz),28.93,23.83;19F NMR(376MHz,Chloroform-d)δ-108.12;HRMS(ESI)m/z:[M+Na]+calcd for C30H26FNONa 458.1896;found458.1881。
(3)化合物(I-3)4-叔丁基-N-(3-异丙基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.70-7.65(m,2H),7.63(d,J=2.2Hz,1H),7.53-7.45(m,3H),7.41-7.26(m,10H),7.02(s,1H),5.73(d,J=1.2Hz,1H),5.44(d,J=1.3Hz,1H),3.17(hept,J=6.9Hz,1H),1.34(s,9H),1.30(d,J=6.8Hz,6H);13C NMR(101MHz,Chloroform-d)δ166.28,155.08,147.92,147.57,141.04,140.92,140.62,140.40,131.42,131.22,128.90,128.78,128.02,127.52,127.40,127.20,127.01,126.52,125.34,124.92,116.81,35.01,31.28,28.91,23.83;HRMS(ESI)m/z:[M+Na]+calcd for C34H35NONa496.2616;found 496.2611。
(4)化合物(I-4)4-甲氧基-N-(3-异丙基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.69-7.62(m,2H),7.60(d,J=2.2Hz,1H),7.52-7.42(m,3H),7.41-7.30(m,3H),7.25(s,5H),6.88(s,1H),6.79(d,J=8.7Hz,2H),5.68(d,J=1.3Hz,1H),5.42(d,J=1.3Hz,1H),3.82(s,3H),3.14(hept,J=6.9Hz,1H),1.28(d,J=6.8Hz,6H);13C NMR(101MHz,Chloroform-d)δ165.87,162.30,148.07,147.52,141.06,140.89,140.70,140.33,131.29,129.01,128.91,128.80,127.99,127.52,127.41,127.23,126.55,126.50,124.97,116.97,113.59,55.53,28.89,23.83;HRMS(ESI)m/z:[M+Na]+calcd for C31H29NO2Na 470.2096;found470.2093。
(5)化合物(I-5)N-(3-异丙基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)噻吩-2-甲酰胺
1H NMR(400MHz,DMSO-d6)δ9.53(s,1H),7.74-7.64(m,3H),7.61(d,J=2.4Hz,2H),7.46(t,J=7.6Hz,2H),7.37(t,J=7.3Hz,1H),7.32-7.14(m,6H),7.09(dd,J=5.0,3.7Hz,1H),5.66(d,J=1.4Hz,1H),5.37(d,J=1.4Hz,1H),3.19(hept,J=6.9Hz,1H),1.24(d,J=6.9Hz,6H);13C NMR(101MHz,DMSO-d6)δ160.52,147.64,146.96,141.32,140.61,139.85,139.50,139.23,132.23,130.76,128.95,128.67,128.00,127.62,127.52,127.33,126.83,126.76,125.92,123.46,116.31,28.19,23.33;HRMS(ESI)m/z:[M+Na]+calcd forC28H25NOSNa 446.1555;found446.1550。
(6)化合物(I-6)N-(3-异丙基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)乙酰胺
1H NMR(400MHz,Chloroform-d)δ7.65-7.58(m,2H),7.56(d,J=2.1Hz,1H),7.48-7.42(m,3H),7.41-7.26(m,7H),6.28(s,1H),5.72(d,J=1.3Hz,1H),5.39(d,J=1.3Hz,1H),3.09(hept,J=6.8Hz,1H),1.70(s,3H),1.26(d,J=6.8Hz,6H);13C NMR(101MHz,Chloroform-d)δ172.8 2,169.34,148.84,148.18,147.89,147.46,142.38,141.88,140.99,140.75,140.54,140.35,140.15,131.84,131.03,129.05,128.89,128.80(d,J=1.7Hz),128.24,128.07,127.95,127.53,127.38,127.32,127.13,126.44,126.36,124.99,124.96,116.93,116.84,28.76,28.31,24.50,23.79,22.92,22.75,20.04;HRMS(ESI)m/z:[M+Na]+calcd for C25H25NONa 378.1834;found 378.1826。
(7)化合物(I-7)N-(3-(1-(4-氟苯基)乙烯基)-5-异丙基-[1,1'-联苯]-4-基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.69-7.60(m,3H),7.53-7.42(m,6H),7.41-7.31(m,3H),7.25-7.17(m,2H),7.01(s,1H),6.89(t,J=8.7Hz,2H),5.64(s,1H),5.40(s,1H),3.16(hept,J=6.9Hz,1H),1.29(d,J=6.9Hz,6H);13C NMR(101MHz,Chloroform-d)δ166.45,162.67(d,J=247.5Hz),147.50,147.11,141.09,140.92,140.07,136.67(d,J=3.3Hz),134.22,131.75,131.03,128.96,128.54,128.26(d,J=8.0Hz),127.63,127.40,127.17,127.04,125.13,116.71,115.51(d,J=21.6Hz),28.93,23.81;19F NMR(376MHz,Chloroform-d)δ-114.29;HRMS(ESI)m/z:[M+Na]+calcd for C30H26FNONa 458.1896;found458.1887。
(8)化合物(I-8)N-(3-(1-(环己基)乙烯基)-5-异丙基-[1,1'-联苯]-4-基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.91-7.84(m,2H),7.65-7.59(m,2H),7.59-7.42(m,7H),7.40-7.33(m,1H),7.23(d,J=2.1Hz,1H),5.16(s,1H),5.01(s,1H),3.22(hept,J=6.9Hz,1H),2.17-2.03(m,1H),1.84-1.62(m,5H),1.31(d,J=6.9Hz,6H),1.20-1.05(m,5H);13C NMR(101MHz,Chloroform-d)δ167.13,154.61,146.93,141.85,141.22,140.21,134.86,131.86,130.37,128.89,128.86,127.43,127.40,127.26,125.68,124.14,112.32,44.79,32.41,29.09,26.70,26.27,23.91;HRMS(ESI)m/z:[M+H]+calcd for C30H34NO424.2640;found 424.2630。
(9)化合物(I-9)N-(3-(1-(4-溴苯基)乙烯基)-5-异丙基-[1,1'-联苯]-4-基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.68-7.62(m,3H),7.51-7.30(m,11H),7.12(d,J=8.2Hz,2H),7.04(s,1H),5.68(s,1H),5.45(s,1H),3.17(hept,J=6.8Hz,1H),1.30(d,J=6.9Hz,6H);13C NMR(101MHz,Chloroform-d)δ166.42,147.51,147.16,141.11,140.85,139.79,139.57,134.10,131.75,131.73,131.03,128.94,128.51,128.23,127.64,127.37,127.21,127.02,125.18,122.00,117.47,28.90,23.77;HRMS(ESI)m/z:[M+Na]+calcd forC30H26BrNONa 518.1095;found 518.1089。
(10)化合物(I-10)N-(3-(1-(3-溴苯基)乙烯基)-5-异丙基-[1,1'-联苯]-4-基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.-7.61(m,3H),7.51-7.33(m,11H),7.16-7.07(m,2H),6.97(s,1H),5.67(s,1H),5.48(s,1H),3.16(hept,J=6.9Hz,1H),1.29(d,J=6.9Hz,6H);13C NMR(101MHz,Chloroform-d)δ166.40,147.61,147.03,143.02,141.21,140.86,139.84,134.07,131.78,131.00,130.88,130.22,129.47,128.96,128.63,127.67,127.42,127.25,127.05,125.40,125.26,123.01,118.29,28.92,23.78;HRMS(ESI)m/z:[M+Na]+calcd for C30H26BrNONa518.1095;found 518.1088。
(11)化合物(I-11)N-(3-(1-(4-氯苯基)乙烯基)-5-异丙基-[1,1'-联苯]-4-基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.69-7.61(m,3H),7.51-7.33(m,9H),7.21-7.12(m,4H),7.03(s,1H),5.67(s,1H),5.44(s,1H),3.17(hept,J=6.9Hz,1H),1.30(d,J=6.9Hz,6H);13C NMR(101MHz,Chloroform-d)δ166.45,147.53,147.11,141.13,140.87,139.88,139.09,134.16,133.84,131.75,131.05,128.95,128.78,128.52,127.91,127.64,127.38,127.20,127.03,125.18,117.36,28.92,23.78;HRMS(ESI)m/z:[M+Na]+calcd forC30H26ClNONa 474.1601;found 474.1596。
(12)化合物(I-12)N-(3-(1-(3-甲氧基苯基)乙烯基)-5-异丙基-[1,1'-联苯]-4-基)苯甲酰胺1H NMR(400MHz,Chloroform-d)δ7.67(dd,J=8.3,1.3Hz,2H),7.62(d,J=2.1Hz,1H),7.53(d,J=2.2Hz,1H),7.51-7.38(m,6H),7.36-7.31(m,2H),7.18(t,J=7.8Hz,1H),7.00(s,1H),6.86–6.78(m,3H),5.69(d,J=1.2Hz,1H),5.45(d,J=1.2Hz,1H),3.65(s,3H),3.16(hept,J=6.8Hz,1H),1.30(d,J=6.9Hz,6H);13C NMR(101MHz,Chloroform-d)δ166.31,159.97,148.05,147.49,142.31,141.02,141.00,140.32,134.18,131.60,131.09,129.82,128.92,128.42,127.56,127.41,127.21,127.15,125.02,118.99,117.33,113.89,111.89,55.27,28.90,23.82;HRMS(ESI)m/z:[M+Na]+calcd forC31H29NO2Na 470.2096;found 470.2092。
(13)化合物(I-13)N-(3-甲基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.69-7.64(m,2H),7.57(d,J=2.2Hz,1H),7.52(d,J=2.2Hz,1H),7.50-7.43(m,3H),7.43-7.37(m,3H),7.36-7.26(m,7H),7.15(s,1H),5.75(d,J=1.2Hz,1H),5.43(d,J=1.2Hz,1H),2.38(s,3H);13C NMR(101MHz,Chloroform-d)δ165.53,147.79,140.63,140.36,140.27,139.43,136.96,134.19,132.42,131.62,129.58,128.92,128.87,128.45,128.20,127.55,127.34,127.21,127.09,126.56,116.93,19.08;HRMS(ESI)m/z:[M+Na]+calcd for C28H23NONa 412.1677;found 412.1669。
(14)化合物(I-14)N-(3-叔丁基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.72(d,J=2.1Hz,1H),7.67-7.63(m,2H),7.57(d,J=2.1Hz,1H),7.50-7.42(m,3H),7.40-7.34(m,1H),7.34-7.27(m,4H),7.26-7.15(m,5H),6.85(s,1H),5.67(d,J=1.2Hz,1H),5.49(d,J=1.2Hz,1H),1.41(s,9H);13C NMR(101MHz,Chloroform-d)δ166.60,148.84,147.99,143.72,141.27,141.13,141.11,134.61,132.39,131.59,128.93,128.72,128.52,128.47,127.74,127.59,127.51,127.09,126.13,126.07,117.38,35.65,31.21;HRMS(ESI)m/z:[M+Na]+calcd for C31H29NONa454.2147;found 454.2138。
(15)化合物(I-15)N-(2-(叔丁基)-6-(1-苯基乙烯基)苯基)苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.53(dd,J=7.3,2.3Hz,1H),7.47-7.41(m,1H),7.41-7.34(m,2H),7.33-7.28(m,4H),7.26-7.17(m,3H),7.16-7.11(m,2H),6.83(s,1H),5.64(d,J=1.2Hz,1H),5.42(d,J=1.2Hz,1H),1.37(s,9H);13C NMR(101MHz,Chloroform-d)δ166.46,148.56,147.93,143.37,141.37,134.65,133.15,131.53,129.76,128.67,128.50,128.33,127.66,127.05,127.00,126.07,117.20,35.47,31.18;HRMS(ESI)m/z:[M+Na]+calcd for C25H25NONa378.1834;found 378.1829。
(16)化合物(I-16)N-(3-(叔丁基)-5-(1-苯基乙烯基)-[1,1'-联苯基]-4-基)-4-氟苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.74(d,J=2.2Hz,1H),7.69-7.64(m,2H),7.59(d,J=2.2Hz,1H),7.51-7.45(m,2H),7.42-7.36(m,1H),7.34-7.27(m,3H),7.25-7.16(m,4H),7.04-6.94(m,2H),6.78(s,1H),5.68(d,J=1.2Hz,1H),5.50(d,J=1.2Hz,1H),1.42(s,9H);13C NMR(101MHz,Chloroform-d)δ165.50,164.86(d,J=251.9Hz),148.80,147.98,143.60,141.26,141.23,141.07,132.22,130.74(d,J=3.1Hz),129.45(d,J=9.0Hz),128.95,128.78,128.52,127.80,127.64,127.51,126.13,126.09,117.51,115.55(d,J=21.9Hz),35.64,31.21;19F NMR(376MHz,Chloroform-d)δ-108.11;HRMS(ESI)m/z:[M+Na]+calcd for C31H28FNONa 472.2053;found 472.2049。
(17)化合物(I-17)N-(3-(叔丁基)-5-(1-苯基乙烯基)-[1,1'-联苯基]-4-基)-4-叔丁基苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.72(d,J=2.2Hz,1H),7.67-7.62(m,2H),7.56(d,J=2.2Hz,1H),7.50-7.44(m,2H),7.41-7.35(m,1H),7.34-7.30(m,2H),7.27(s,2H),7.26-7.18(m,5H),6.82(s,1H),5.67(d,J=1.2Hz,1H),5.48(d,J=1.2Hz,1H),1.41(s,9H),1.33(s,9H);13C NMR(101MHz,Chloroform-d)δ166.65,155.03,148.92,147.93,143.81,141.29,141.19,141.01,132.56,131.84,128.92,128.67,128.41,127.71,127.57,127.52,126.94,126.19,126.02,125.43,117.25,35.67,35.04,31.31,31.23;HRMS(ESI)m/z:[M+Na]+calcd for C35H37NONa 510.2773;found 510.2766。
(18)化合物(I-18)N-(3-(叔丁基)-5-(1-苯基乙烯基)-[1,1'-联苯基]-4-基)-2-萘甲酰胺
1H NMR(400MHz,Chloroform-d)δ7.84(d,J=7.2Hz,1H),7.81-7.72(m,3H),7.67(d,J=7.3Hz,2H),7.63-7.58(m,2H),7.57-7.43(m,5H),7.42-7.31(m,2H),7.26-7.20(m,4H),7.00(s,1H),5.69(s,1H),5.53(s,1H),1.43(s,9H);13C NMR(101MHz,Chloroform-d)δ166.62,148.87,148.00,143.71,141.42,141.19,141.15,134.89,132.55,132.42,131.85,129.07,128.95,128.86,128.58,128.43,127.86,127.80,127.76,127.61,127.53,127.52,126.77,126.18,126.14,123.91,117.55,35.67,31.23;HRMS(ESI)m/z:[M+Na]+calcd forC35H31NONa 504.2303;found504.2292。
需要说明的是,本发明结构式(II)所示化合物N-(2-硝基硒苯基)丁二酰亚胺根据现有技术(J.Am.Chem.Soc.2010,132,15752-15765)的合成方法合成。
需要说明的是,本发明结构式(Ⅲ)所示化合物根据现有技术(Helv.Chim.Acta2017,100,e1700158)的合成方法合成。
本发明的合成方法制备的含硒芳基的手性4H-3,1-苯并噁嗪类化合物的结构式选自以下其中的一种:
其中,Ph为苯基;t-Bu为叔丁基;i-Pr为异丙基;Ar为2-硝基苯基。
以下结合具体实施方式和附图对本发明的技术方案作进一步详细描述:
实施例1:化合物1的制备
将0.1mmol N-(3-异丙基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体1,收率为73%,对映选择性为93%ee。
1H NMR(400MHz,Chloroform-d)δ8.24(d,J=6.7Hz,2H),8.17(dd,J=8.3,1.5Hz,1H),7.59-7.36(m,12H),7.36-7.25(m,5H),7.24-7.19(m,1H),4.06-3.89(m,3H),1.36(d,J=3.3Hz,3H),1.34(d,J=3.4Hz,3H);13C NMR(101MHz,Chloroform-d)δ154.78,147.26,144.84,141.93,141.20,139.30,135.74,133.67,133.39,132.69,131.55,129.74,128.93,128.68,128.60,128.47,128.22,127.82,127.45,127.18,126.34,126.23,125.68,125.30,120.91,83.06,37.07,27.62,23.77,23.33;HRMS(ESI)m/z:[M+H]+calcd for C36H31N2O3Se619.1500;found 619.1495;HPLC(Daicel Chiralpak AS-H,n-hexane/i-PrOH=90:10,1.0mL/min,254nm):tR(minor)=6.86min,tR(major)=9.23min,93%ee;SpecificRotation:
实施例2:化合物2的制备
将0.1mmol 4-氟-N-(3-异丙基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼乙醚溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体2,收率为83%,对映选择性为91%ee。
1H NMR(400MHz,Chloroform-d)δ8.27-8.17(m,3H),7.60-7.47(m,6H),7.47-7.39(m,3H),7.38-7.29(m,4H),7.26-7.22(m,2H),7.16-7.07(m,2H),4.04-3.91(m,3H),1.37(d,J=4.6Hz,3H),1.35(d,J=4.7Hz,3H);13C NMR(101MHz,Chloroform-d)δ165.06(d,J=252.0Hz),153.96,147.29,144.79,141.79,141.16,139.36,135.59,133.68,133.27,130.45(d,J=8.9Hz),129.70,128.95,128.90(d,J=3.8Hz),128.72,128.69,127.71,127.49,127.18,126.39,126.23,125.75,125.35,120.95,115.58(d,J=21.8Hz),83.20,36.96,27.60,23.74,23.35;19F NMR(376MHz,Chloroform-d)δ-108.20;HRMS(ESI)m/z:[M+H]+calcd for C36H30FN2O3Se 637.1406;found 637.1394;HPLC(Daicel Chiralpak AS-H,n-hexane/i-PrOH=95:5,1.0mL/min,254nm):tR(minor)=8.05min,tR(major)=12.62min,91%ee;
实施例3:化合物3的制备
将0.1mmol 4-叔丁基-N-(3-异丙基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体3,收率为66%,对映选择性为91%ee。
1H NMR(400MHz,Chloroform-d)δ8.19(d,J=8.2Hz,3H),7.62-7.51(m,6H),7.50-7.39(m,5H),7.38-7.28(m,4H),7.25(d,J=7.8Hz,2H),4.07-3.90(m,3H),1.41-1.33(m,15H);13C NMR(101MHz,Chloroform-d)δ155.08,154.88,147.26,144.69,141.94,141.29,139.06,135.93,133.67,133.54,129.92,129.75,128.92,128.66,128.54,128.11,127.89,127.40,127.18,126.34,126.29,125.63,125.48,125.25,120.88,82.88,37.09,35.12,31.33,27.69,23.74,23.29;HRMS(ESI)m/z:[M+H]+calcd for C40H39N2O3Se 675.2126;found 675.2114;HPLC(Daicel Chiralpak AD,n-hexane/i-PrOH=97:3,1.0mL/min,254nm):tR(minor)=5.97min,tR(major)=7.18min,91%ee;Specific Rotation:
实施例4:化合物4的制备
将0.1mmol 4-甲氧基-N-(3-异丙基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体4,收率为67%,对映选择性为94%ee。
1H NMR(400MHz,Chloroform-d)δ8.20(d,J=8.6Hz,3H),7.60-7.49(m,6H),7.42(q,J=7.8Hz,3H),7.32(q,J=8.9Hz,4H),7.25(d,J=4.0Hz,2H),6.95(d,J=8.9Hz,2H),4.06–3.89(m,3H),3.87(s,3H),1.36(d,J=4.2Hz,3H),1.34(d,J=4.3Hz,3H);13C NMR(101MHz,Chloroform-d)δ162.52,154.80,147.28,144.52,141.87,141.32,138.82,136.05,133.68,133.53,130.10,129.78,128.92,128.66,128.55,127.87,127.37,127.17,126.36,126.28,125.66,125.22,120.84,113.88,82.86,55.57,37.03,27.58,23.76,23.33;HRMS(ESI)m/z:[M+H]+calcd for C37H33N2O4Se 649.1606;found 649.1595;HPLC(Daicel Chiralpak AS-H,n-hexane/i-PrOH=90:10,1.0mL/min,254nm):tR(minor)=8.95min,tR(major)=12.06min,94%ee;Specific Rotation:
实施例5:化合物5的制备
将0.1mmol N-(3-异丙基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)噻吩-2-甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体5,收率为77%,对映选择性为92%ee。
1H NMR(400MHz,Chloroform-d)δ8.19(d,J=8.8Hz,1H),7.78(d,J=3.7Hz,1H),7.62(d,J=8.1Hz,1H),7.57-7.48(m,5H),7.47-7.39(m,4H),7.37-7.22(m,6H),7.08(t,J=4.4Hz,1H),3.98(d,J=12.6Hz,1H),3.93-3.81(m,2H),1.33(d,J=5.4Hz,6H);13C NMR(101MHz,Chloroform-d)δ151.62,147.25,144.60,141.86,141.19,139.08,137.46,135.89,133.71,133.49,130.67,130.15,129.79,128.94,128.70,128.68,127.97,127.61,127.45,127.18,126.35,126.20,125.70,125.40,120.98,83.46,36.97,27.69,23.80,23.22;HRMS(ESI)m/z:[M+H]+calcd for C34H29N2O3SSe 625.1064;found 625.1057;HPLC(Daicel Chiralpak AS-H,n-hexane/i-PrOH=70:30,1.0mL/min,254nm):tR(minor)=5.67min,tR(major)=7.56min,92%ee;Specific Rotation:
实施例6:化合物6的制备
将0.1mmol N-(3-异丙基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)乙酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-5℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体6,收率为85%,对映选择性为91%ee。
1H NMR(400MHz,Chloroform-d)δ8.23(d,J=8.3Hz,1H),7.58(d,J=8.1Hz,1H),7.54–7.39(m,8H),7.39–7.27(m,5H),7.17(s,1H),3.90(d,J=12.3Hz,1H),3.85–3.74(m,2H),2.20(s,3H),1.28(d,J=4.7Hz,3H),1.26(d,J=5.1Hz,3H);13C NMR(101MHz,Chloroform-d)δ158.26,147.28,144.15,142.62,141.22,138.91,135.41,133.69,133.57,129.71,128.90,128.68,128.62,127.38,127.17,126.72,126.43,126.15,125.71,125.24,120.97,82.61,37.06,26.92,23.78,23.40,22.23;HRMS(ESI)m/z:[M+H]+calcd forC31H29N2O3Se 557.1343;found 557.1337;HPLC(Daicel Chiralpak OD-H,n-hexane/i-PrOH=95:5,1.0mL/min,254nm):tR(minor)=10.43min,tR(major)=12.18min,91%ee;Specific Rotation:
实施例7:化合物7的制备
将0.1mmol N-(3-(1-(4-氟苯基)乙烯基)-5-异丙基-[1,1'-联苯]-4-基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体7,收率为85%,对映选择性为90%ee。
1H NMR(400MHz,Chloroform-d)δ8.26-8.16(m,3H),7.59-7.52(m,4H),7.51-7.38(m,8H),7.38-7.31(m,1H),7.26-7.20(m,2H),7.00(t,J=8.6Hz,2H),4.05-3.93(m,2H),3.90(d,J=12.5Hz,1H),1.37(d,J=1.6Hz,3H),1.35(d,J=1.7Hz,3H);13C NMR(101MHz,Chloroform-d)δ162.71(d,J=248.1Hz),154.65,147.28,144.99,141.08,139.44,137.72(d,J=3.3Hz),135.68,133.71,133.10,132.55,131.66,129.70,128.96,128.52,128.26(d,J=8.4Hz),128.17,127.72,127.54,127.16,126.37,125.80,125.45,120.76,115.58(d,J=21.6Hz),82.63,36.95,27.64,23.74,23.33;19F NMR(376MHz,Chloroform-d)δ-113.32;HRMS(ESI)m/z:[M+H]+calcd for C36H30FN2O3Se 637.1406;found 637.1398;HPLC(Daicel Chiralpak OD-H,n-hexane/i-PrOH=95:5,1.0mL/min,254nm):tR(minor)=11.67min,tR(major)=9.37min,90%ee;Specific Rotation:
实施例8:化合物8的制备
将0.1mmol N-(3-(1-(环己基)乙烯基)-5-异丙基-[1,1'-联苯]-4-基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼乙醚溶于2mL氘代氯仿在-10℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体8,收率为51%,对映选择性为91%ee。
1H NMR(400MHz,Chloroform-d)δ8.19-8.15(m,2H),8.09(dd,J=8.2,1.5Hz,1H),7.52-7.39(m,8H),7.37-7.26(m,3H),7.19-7.10(m,2H),4.01(hept,J=7.0Hz,1H),3.71(d,J=12.5Hz,1H),3.57(d,J=12.5Hz,1H),2.29–2.19(m,1H),2.07-1.98(m,1H),1.92-1.69(m,4H),1.55-1.42(m,1H),1.38(d,J=3.1Hz,3H),1.36(d,J=3.1Hz,3H),1.31-1.07(m,4H);13C NMR(101MHz,Chloroform-d)δ154.50,147.35,144.53,141.29,138.87,136.03,133.37,133.15,132.83,131.29,129.68,128.84,128.37,127.96,127.30,127.06,126.16,126.12,125.58,124.65,120.39,84.91,46.91,35.02,27.62,27.51,26.51,26.48,26.30,23.70,23.44;HRMS(ESI)m/z:[M+H]+calcd for C36H37N2O3Se 625.1969;found 625.1965;HPLC(Daicel Chiralpak OD-H,n-hexane/i-PrOH=99:1,1.0mL/min,254nm):tR(minor)=8.52min,tR(major)=7.33min,91%ee;Specific Rotation:
实施例9:化合物9的制备
将0.1mmol N-(3-(1-(4-溴苯基)乙烯基)-5-异丙基-[1,1'-联苯]-4-基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体9,收率为70%,对映选择性为90%ee。
1H NMR(400MHz,Chloroform-d)δ8.26-8.13(m,3H),7.58-7.51(m,4H),7.51-7.31(m,11H),7.25-7.21(m,2H),4.04-3.92(m,2H),3.88(d,J=12.5Hz,1H),1.35(d,J=6.9Hz,6H);13C NMR(101MHz,Chloroform-d)δ154.58,147.27,145.05,141.05,140.95,139.52,135.63,133.74,133.03,132.46,131.82,131.70,129.68,128.98,128.54,128.16,128.07,127.57,127.42,127.18,126.39,125.83,125.54,122.87,120.68,82.63,36.71,27.64,23.74,23.31;HRMS(ESI)m/z:[M+H]+calcd for C36H30BrN2O3Se 697.0605;found697.0598;HPLC(Daicel Chiralpak OD-H,n-hexane/i-PrOH=90:10,1.0mL/min,290nm):tR(minor)=9.84min,tR(major)=8.04min,90%ee;Specific Rotation:
实施例10:化合物10的制备
将0.1mmol N-(3-(1-(3-溴苯基)乙烯基)-5-异丙基-[1,1'-联苯]-4-基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-10℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体10,收率为75%,对映选择性为92%ee。
1H NMR(400MHz,Chloroform-d)δ8.28-8.15(m,3H),7.65(s,1H),7.59-7.39(m,12H),7.36(t,J=7.3Hz,1H),7.27-7.17(m,3H),4.06-3.93(m,2H),3.89(d,J=12.5Hz,1H),1.37(d,J=6.9Hz,6H);13C NMR(101MHz,Chloroform-d)δ154.56,147.31,145.06,144.21,141.08,139.58,135.58,133.74,132.99,132.44,131.81,131.73,130.18,129.73,129.56,128.98,128.56,128.21,127.57,127.22,126.40,125.86,125.65,124.98,123.03,120.77,82.56,36.78,27.66,23.75,23.33;HRMS(ESI)m/z:[M+H]+calcd forC36H30BrN2O3Se 697.0605;found 697.0591;HPLC(Daicel Chiralpak OD-H,n-hexane/i-PrOH=95:5,1.0mL/min,254nm):tR(minor)=11.99min,tR(major)=9.59min,92%ee;Specific Rotation:
实施例11:化合物11的制备
将0.1mmol N-(3-(1-(4-联苯基)乙烯基)-5-异丙基-[1,1'-联苯]-4-基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体11,收率为67%,对映选择性为92%ee。
1H NMR(400MHz,Chloroform-d)δ8.25-8.14(m,3H),7.58-7.51(m,4H),7.51-7.37(m,8H),7.34(t,J=7.3Hz,1H),7.30-7.26(m,2H),7.25-7.21(m,2H),4.05-3.91(m,2H),3.88(d,J=12.4Hz,1H),1.35(d,J=6.9Hz,6H);13C NMR(101MHz,Chloroform-d)δ154.59,147.30,145.05,141.06,140.42,139.51,135.64,134.63,133.73,133.03,132.49,131.69,129.71,128.98,128.86,128.54,128.17,127.78,127.57,127.50,127.18,126.39,125.83,125.53,120.70,82.60,36.78,27.65,23.74,23.32;HRMS(ESI)m/z:[M+H]+calcd forC36H30ClN2O3Se 653.1110;found653.1099;HPLC(Daicel Chiralpak OD-H,n-hexane/i-PrOH=95:5,1.0mL/min,254nm):tR(minor)=12.01min,tR(major)=9.51min,92%ee;Specific Rotation:
实施例12:化合物12的制备
将0.1mmol N-(3-(1-(3-甲氧基苯基)乙烯基)-5-异丙基-[1,1'-联苯]-4-基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体12,收率为65%,对映选择性为92%ee。
1H NMR(400MHz,Chloroform-d)δ8.29-8.24(m,2H),8.19(dd,J=8.3,1.5Hz,1H),7.62-7.53(m,4H),7.50-7.39(m,6H),7.38-7.32(m,1H),7.31(d,J=1.9Hz,1H),7.28-7.21(m,2H),7.11-7.05(m,2H),6.83(dd,J=8.2,1.5Hz,1H),4.07-3.88(m,3H),3.70(s,3H),1.38(d,J=1.5Hz,3H),1.36(d,J=1.4Hz,3H);13C NMR(101MHz,Chloroform-d)δ159.74,154.78,147.25,144.82,143.56,141.24,139.35,135.71,133.68,133.47,132.68,131.56,129.75,129.70,128.93,128.48,128.20,127.79,127.45,127.21,126.35,125.68,125.35,120.82,118.56,113.60,112.59,82.94,55.32,37.06,27.61,23.80,23.30;HRMS(ESI)m/z:[M+H]+calcd for C37H33N2O4Se 649.1606;found 649.1592;HPLC(Daicel Chiralpak AD-H,n-hexane/i-PrOH=95:5,1.0mL/min,290nm):tR(minor)=7.43min,tR(major)=5.79min,92%ee;Specific Rotation:
实施例13:化合物13的制备
将0.1mmol N-(3-甲基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体13,收率为77%,对映选择性为90%ee。
1H NMR(400MHz,Chloroform-d)δ8.24(d,J=6.8Hz,2H),8.16(d,J=8.2Hz,1H),7.58(d,J=8.1Hz,1H),7.55-7.44(m,6H),7.44-7.36(m,5H),7.34-7.24(m,5H),7.24-7.18(m,1H),3.99(d,J=12.5Hz,1H),3.94(d,J=12.5Hz,1H),2.59(s,3H);13C NMR(101MHz,Chloroform-d)δ155.08,147.24,141.94,140.77,138.98,136.95,134.77,133.66,133.33,132.53,131.61,129.79,129.74,128.92,128.69,128.62,128.45,128.20,127.70,127.47,127.09,126.32,126.12,125.70,121.05,83.11,37.03,17.49;HRMS(ESI)m/z:[M+H]+calcdfor C34H27N2O3Se591.1187;found 591.1177;HPLC(Daicel Chiralpak AD-H,n-hexane/i-PrOH=97:3,1.0mL/min,254nm):tR(minor)=10.10min,tR(major)=12.18min,90%ee;Specific Rotation:
实施例14:化合物14的制备
将0.1mmol N-(3-叔丁基-5-(1-苯基乙烯基)-[1,1'-联苯]-4-基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体14,收率为85%,对映选择性为95%ee。
1H NMR(400MHz,Chloroform-d)δ8.28-8.22(m,2H),8.19(dd,J=8.2,1.5Hz,1H),7.65(d,J=1.9Hz,1H),7.62-7.41(m,11H),7.38-7.28(m,5H),7.26-7.22(m,1H),4.02(d,J=12.5Hz,1H),3.95(d,J=12.4Hz,1H),1.66(s,9H);13C NMR(101MHz,Chloroform-d)δ152.80,147.23,145.69,142.09,141.33,138.69,137.15,133.68,133.45,132.82,131.45,129.69,128.94,128.74,128.65,128.59,128.53,128.10,127.42,127.22,126.36,126.31,126.11,125.67,121.64,82.91,37.17,36.28,31.14;HRMS(ESI)m/z:[M+H]+calcd forC37H33N2O3Se 633.1656;found 633.1649;HPLC(Daicel Chiralpak OD-H,n-hexane/i-PrOH=95:5,1.0mL/min,254nm):tR(minor)=10.01min,tR(major)=8.39min,95%ee;SpecificRotation:
实施例15:化合物15的制备
将0.1mmol N-(2-(叔丁基)-6-(1-苯基乙烯基)苯基)苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体15,收率为87%,对映选择性为90%ee。
1H NMR(400MHz,Chloroform-d)δ8.25-8.21(m,2H),8.19(dd,J=8.3,1.5Hz,1H),7.57(dd,J=8.2,1.3Hz,1H),7.52-7.38(m,7H),7.36-7.27(m,3H),7.26-7.21(m,1H),7.18(t,J=7.7Hz,1H),7.11(dd,J=7.7,1.5Hz,1H),3.95(d,J=12.3Hz,1H),3.89(d,J=12.3Hz,1H),1.60(s,9H);13C NMR(101MHz,Chloroform-d)δ152.70,147.15,145.35,142.16,137.76,133.67,133.52,132.83,131.39,129.61,128.57,128.49,128.29,128.07,127.02,126.35,126.29,126.00,125.62,122.90,82.70,37.02,36.09,31.12;HRMS(ESI)m/z:[M+H]+calcd for C31H29N2O3Se 557.1343;found 557.1345;HPLC(Daicel ChiralpakOD-H,n-hexane/i-PrOH=90:10,1.0mL/min,254nm):tR(minor)=9.29min,tR(major)=7.43min,90%ee;Specific Rotation:
实施例16:化合物16的制备
将0.1mmol N-(3-(叔丁基)-5-(1-苯基乙烯基)-[1,1'-联苯基]-4-基)-4-氟苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体16,收率为74%,对映选择性为96%ee。
1H NMR(400MHz,Chloroform-d)δ8.25-8.15(m,3H),7.63(d,J=2.0Hz,1H),7.58-7.47(m,5H),7.46-7.38(m,3H),7.37-7.30(m,4H),7.26(s,1H),7.24(dd,J=8.8,1.7Hz,1H),7.12(t,J=8.7Hz,2H),3.99(d,J=12.4Hz,1H),3.92(d,J=12.4Hz,1H),1.62(s,9H);13C NMR(101MHz,Chloroform-d)δ164.98(d,J=252.0Hz),152.00,147.27,145.62,141.94,141.27,138.75,137.00,133.69,133.30,130.28(d,J=8.8Hz),129.66,129.02(d,J=3.0Hz),128.95,128.69,128.67,128.63,127.46,127.21,126.39,126.31,126.16,125.73,121.67,115.63(d,J=21.9Hz),83.05,37.06,36.26,31.13;19F NMR(376MHz,Chloroform-d)δ-108.34;HRMS(ESI)m/z:[M+H]+calcd for C37H32FN2O3Se 651.1562;found651.1559;HPLC(Daicel Chiralpak OD-H,n-hexane/i-PrOH=95:5,1.0mL/min,254nm):tR(minor)=10.72min,tR(major)=9.22min,96%ee;Specific Rotation:
实施例17:化合物17的制备
将0.1mmol N-(3-(叔丁基)-5-(1-苯基乙烯基)-[1,1'-联苯基]-4-基)-4-叔丁基苯甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼乙醚溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体17,收率为77%,对映选择性为94%ee。
1H NMR(400MHz,Chloroform-d)δ8.20-8.14(m,3H),7.62(d,J=2.0Hz,1H),7.58(dd,J=8.2,1.3Hz,1H),7.54-7.50(m,4H),7.50-7.46(m,2H),7.45-7.38(m,3H),7.37-7.29(m,4H),7.26-7.21(m,2H),4.00(d,J=12.4Hz,1H),3.92(d,J=12.4Hz,1H),1.63(s,9H),1.36(s,9H);13C NMR(101MHz,Chloroform-d)δ154.98,152.88,147.23,145.54,142.08,141.40,138.46,137.29,133.68,133.60,130.04,129.70,128.93,128.82,128.64,128.54,128.01,127.37,127.21,126.38,126.36,126.06,125.61,125.55,121.61,82.75,37.16,36.28,35.13,31.34,31.10;HRMS(ESI)m/z:[M+H]+calcd for C41H41N2O3Se689.2282;found 689.2275;HPLC(Daicel Chiralpak IB,n-hexane/i-PrOH=99:1,1.0mL/min,254nm):tR(minor)=14.87min,tR(major)=10.50min,94%ee;Specific Rotation:
实施例18:化合物18的制备
将0.1mmol N-(3-(叔丁基)-5-(1-苯基乙烯基)-[1,1'-联苯基]-4-基)-2-萘甲酰胺、0.12mmol N-(2-硝基硒苯基)丁二酰亚胺和0.01mmol催化剂,以及0.1mmol三氟化硼四氢呋喃溶于2mL氘代氯仿在-20℃下搅拌反应84小时,反应结束后通过柱层析硅胶纯化粗混合物,得到黄色固体18,收率为78%,对映选择性为96%ee。
1H NMR(400MHz,Chloroform-d)δ8.66(s,1H),8.35(dd,J=8.7,1.7Hz,1H),8.17(dd,J=8.3,1.5Hz,1H),7.97-7.93(m,1H),7.89(t,J=8.4Hz,2H),7.68(d,J=2.0Hz,1H),7.64(dd,J=8.2,1.2Hz,1H),7.60-7.53(m,6H),7.49-7.30(m,8H),7.20(ddd,J=8.4,7.2,1.2Hz,1H),4.06(d,J=12.5Hz,1H),3.99(d,J=12.5Hz,1H),1.69(s,9H);13C NMR(101MHz,Chloroform-d)δ152.94,147.22,145.77,142.10,141.34,138.77,137.26,134.95,133.65,133.40,132.96,130.22,129.71,129.32,128.95,128.93,128.68,128.61,128.50,128.20,127.86,127.66,127.45,127.24,126.58,126.38,126.35,126.15,125.66,124.77,121.66,83.03,37.07,36.31,31.16;HRMS(ESI)m/z:[M+H]+calcd for C41H35N2O3Se 683.1813;found 683.1801;HPLC(Daicel Chiralpak OD-H,n-hexane/i-PrOH=95:5,1.0mL/min,254nm):tR(minor)=11.91min,tR(major)=10.30min,96%ee;Specific Rotation:
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (4)
1. 一种含硒芳基的手性4H-3,1-苯并噁嗪类化合物的合成方法, 所述合成方法具体包括以下步骤:
室温下,将1,1-二取代烯烃、硒芳基试剂、催化剂和溶剂加入反应管中,在低温条件下进行反应,加入酸,于氩气氛围中进行反应,后经减压蒸馏、柱色谱提纯,制得含硒芳基的手性4H-3,1-苯并噁嗪类化合物;
所述1,1-二取代烯烃与催化剂的摩尔比为1:0.05~0.15;
所述1,1-二取代烯烃与酸的摩尔比为1:0.5~1.5;
所述低温为-25~-5℃,反应时间为72~96h;
所述1,1-二取代烯烃的化学结构如式(I)所示;所述硒芳基试剂的化学结构如式(II)所示;所述催化剂的化学结构如式(III)所示;所述含硒芳基的手性4H-3,1-苯并噁嗪类化合物的化学结构如式(IV)所示;
其中,R1选自氢、C1~6烷基、C1~6烷氧基、苯基、取代苯基、噻吩基或者2-萘基;
R2选自环己基、苯基或者取代苯基;
R3选自氢、C1~6烷基、C1~6烷氧基或者苯基;
R4选自氢、C1~6烷基或者C1~6烷氧基;
所述酸为三氟化硼四氢呋喃或三氟化硼乙醚溶液;所述溶剂为氘代氯仿。
2.根据权利要求1所述的一种含硒芳基的手性4H-3,1-苯并噁嗪类化合物的合成方法,其特征是:所述1,1-二取代烯烃与硒芳基试剂的摩尔比为1:0.8~2。
3.根据权利要求1所述的一种含硒芳基的手性4H-3,1-苯并噁嗪类化合物的合成方法,其特征是:反应体系后处理方式为:反应结束后反应体系经过减压蒸馏除去溶剂,随后进行柱层析,以石油醚/乙酸乙酯体积比30~50:1洗脱,收集目标产物的洗脱液后进行减压蒸馏的目标产物。
4.根据权利要求1所述的一种含硒芳基的手性4H-3,1-苯并噁嗪类化合物的合成方法,其特征是:所述含硒芳基的手性4H-3,1-苯并噁嗪类化合物的收率>50%,ee值≥90%。
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