CN112961183B - C3-膦酰基取代苯并氢化呋喃和苯并呋喃化合物及其制备方法 - Google Patents
C3-膦酰基取代苯并氢化呋喃和苯并呋喃化合物及其制备方法 Download PDFInfo
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- CN112961183B CN112961183B CN202110181233.6A CN202110181233A CN112961183B CN 112961183 B CN112961183 B CN 112961183B CN 202110181233 A CN202110181233 A CN 202110181233A CN 112961183 B CN112961183 B CN 112961183B
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- NYENCOMLZDQKNH-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)bismuthanyl trifluoromethanesulfonate Chemical compound [Bi+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F NYENCOMLZDQKNH-UHFFFAOYSA-K 0.000 claims description 11
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- 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
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- 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
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
- C07F9/655354—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
本发明公开了C3‑膦酰基取代苯并氢化呋喃和苯并呋喃化合物及其制备方法,本发明可直接在空气氛围下,通过添加酸,将化合物I和化合物II直接反应得到一系列本发明C3‑膦酰基取代苯并氢化呋喃和苯并呋喃化合物即化合物A和化合物B,本发明制备方法所使用的原料方便制备,反应条件温和,反应唯一副产物为水使得该反应具有原子经济性高、绿色环保等优点,为药物开发奠定基础。
Description
技术领域
本发明涉及有机合成领域,特别是涉及C3-膦酰基取代苯并氢化呋喃和苯并呋喃化合物及其制备方法。
背景技术
苯并呋喃和苯并二氢呋喃是许多药物、天然产物和聚合物中广泛存在的重要骨架,具有显著的生物和药理学活性。如苯并呋喃化合物a是良好的微管蛋白聚合抑制剂,化合物b是潜在的多巴胺受体配体,化合物c具有显著抗菌活性;含有苯并二氢呋喃结构的化合物d具有抗白血病活性,化合物e具有一定的抗氧化活性,化合物f能够抑制产气荚膜杆菌和霍乱弧菌的神经氨酸酶。
含膦化合物,由于引入了杂原子P,使得该化合物在构型以及键的极性上都有了明显的变化,从而具有独特的生物活性。此外,在金属催化方面,含膦化合物可作为配体调节中心金属的电性进而影响金属催化反应的能力。因此,若能够将含膦官能团引入到苯并呋喃和苯并二氢呋喃中,将是一项有意义的工作。
目前制备C3-膦酰基苯并呋喃化合物的方法还十分有限,且主要是通过基于开链合成子的环化反应构建,如下式所示:
由此可见,目前合成C3-膦酰化苯并呋喃的方法大多都是通过环化反应构建,这在制备含有各种取代基的反应前体时更为复杂。此外,这些方法普遍存在催化剂用量较大,产率不高,底物适用范围窄等不足。在此基础上,基于杂环化合物的直接膦酰化策略合成C3-膦酰化苯并呋喃的方法显得十分重要,毕竟有的底物是能够直接商业购买的,且原料的合成步骤较少,而在前人的工作中,该策略报道得很少。因此,开发新的杂环化合物的直接膦酰化策略构建C3-膦酰化苯并呋喃很有必要。
发明内容
本发明解决的主要技术问题是提供C3-膦酰基取代苯并氢化呋喃和苯并呋喃化合物的制备方法,操作简单,底物范围广,实现了C3-膦酰基取代苯并氢化呋喃和苯并呋喃化合物的高效合成。
为了解决上述的技术问题,本发明所采用的技术方案是:
本发明提供了化合物A的制备方法,包含以下内容:将化合物I和化合物II在酸性条件下反应:
X选自O或S;n选自0、1、2、3、4;
R1、R2、R3、R4、R5分别独立选自H、卤素、氰基、硝基、氨基、酯基、酰胺基、磺酰基、取代或非取代的烷基、取代或非取代的杂烷基、取代或非取代的环烷基、取代或非取代的杂环烷基、取代或非取代的芳基、取代或非取代的杂芳基;其中,取代基选自卤素、硝基、羟基、巯基、氨基、氰基、酰胺基、酰基、酯基、磺酰基、烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基。
进一步地,是将化合物I、化合物II、酸、溶剂混合反应。
进一步地,所述化合物II的摩尔用量为化合物I摩尔用量的1~5倍,优选1~3倍。
进一步地,所述酸选自三氟甲磺酸、对甲苯磺酸、高氯酸、三氟乙酸、樟脑磺酸、五氟苯甲酸、三氟甲磺酸盐或高氯酸盐中的一种或几种。
在本发明的具体实施方式中,所述酸选自三氟甲磺酸、对甲苯磺酸、三氟乙酸、五氟苯甲酸、樟脑磺酸、三氟甲磺酸铋、三氟甲磺酸锌、三氟甲磺酸铜、三氟甲磺酸铁、高氯酸钴、三溴化铋中的一种或几种。
应当理解为,本发明中所述“酸”的可选范围包括其中各个化合物可能存在的任意水合物,如六水高氯酸钴、甲苯磺酸一水合物等。
进一步地,所述酸的摩尔用量为化合物I摩尔用量的0.01~3倍,优选0.01~2倍。
进一步地,所述溶剂选自硝基甲烷、二氯甲烷、二氯乙烷、乙腈、甲苯、苯、乙酸乙酯、THF、氯仿、丙酮、乙醚、甲醇、DMF中的一种或几种。
在本发明的具体实施方式中,所述溶剂选自二氯乙烷、乙腈、甲苯、乙酸乙酯、氯仿、丙酮、乙醚、甲醇、DMF中的一种或几种。
进一步地,所述溶剂的用量为,化合物I:溶剂的料液比为0.3mmol:1~15mL,优选为0.3mmol:2~10mL。
进一步地,制备化合物A的反应温度为0℃~120℃,优选0℃~100℃。
在本发明特定的反应条件下,化合物I在酸性条件下,会脱去一分子水,再与化合物II经C3位区域选择性膦酰化反应得到本发明C3-膦酰基取代苯并氢化呋喃,反应机理如下:
反应完后,通过本领域常规的后处理方法(过滤、浓缩、柱层析等)即可得到化合物A。
进一步地,R1、R2、R3、R4分别独立选自H、卤素、硝基、取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的C3~C10环烷基、取代或非取代的3~10元杂环烷基、取代或非取代的6~10元芳基、取代或非取代的5~10元杂芳基;
R5选自H、卤素、氰基、硝基、酰胺基、酰基、酯基、取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的C3~C10环烷基、取代或非取代的3~10元杂环烷基、取代或非取代的6~10元芳基、取代或非取代的5~10元杂芳基;
R1、R2、R3、R4、R5中的取代基选自卤素、硝基、羟基、氨基、氰基、酰胺基、酰基、酯基、磺酰基、烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基。
进一步地,R1、R2、R3、R4分别独立选自取代或非取代的C1~C6烷基、取代或非取代的6~10元芳基、取代或非取代的5~10元杂芳基;
R5选自H、卤素取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的C3~C10环烷基、取代或非取代的3~10元杂环烷基;n选自0、1、2;
R1、R2、R3、R4、R5中的取代基选自卤素、烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基。
进一步地,R1、R2、R3、R4分别独立选自取代或非取代的苄基、取代或非取代的苯基、取代或非取代的萘基、取代或非取代的噻吩基;
R5选自H、卤素、取代或非取代的C1~C6烷基、取代或非取代的2~6元烷氧基、取代或非取代的C3~C10环烷基、取代或非取代的3~10元杂环烷基;
R1、R2、R3、R4、R5中的取代基选自卤素、C1~C6烷基、2~6元烷氧基、C1~C6环烷基、2~6元杂环烷基。
更进一步地,R1、R2、R3、R4分别独立选自取代或非取代的苄基、取代或非取代的苯基、取代或非取代的萘基、取代或非取代的噻吩基;
R5选自H、Br、取代或非取代的C1~C3烷基、取代或非取代的2~3元烷氧基;n选自0、1;
R1、R2、R3、R4、R5中的取代基选自卤素、C1~C3烷基、2~3元烷氧基。
在本发明的具体实施方式中,所述化合物A选自如下结构:
本发明还提供了化合物B的制备方法:通过将上述任一方法反应后的反应体系移除溶剂后,加入第二溶剂反应,化合物B的结构如下:
其中,X、n、R1、R2、R3、R4、R5如前文中任一项所定义;
进一步地,所述第二溶剂选自CF3CH2OH、二氯甲烷、二氯乙烷、氯仿、乙腈、甲苯、DMF中的一种或几种,优选CF3CH2OH、二氯甲烷、甲苯、DMF中的一种或几种。
在本发明的具体实施方式中,所述第二溶剂选自CF3CH2OH。
进一步地,所述第二溶剂的用量为,化合物I:溶剂的料液比为0.3mmol:1~10mL,优选为0.3mmol:2~5mL,更优选为0.3mmol:3mL。
进一步地,加入第二溶剂后的反应温度为70℃~120℃,优选70℃~100℃,更优选80℃。
本发明方法通过一锅法直接由化合物I、化合物II合成得到了化合物B,应当理解的是,若是将第一步得到的化合物A分离纯化,用纯化后的化合物A再通过相同的条件,必然也能制备得到化合物B。
本发明提供了另一种制备化合物B的方法:通过前述任一种方法制得化合物A,将化合物A在酸性条件下转化为化合物B:
其中,X、n、R1、R2、R3、R4、R5如前文中任一项中所定义。
进一步地,是将化合物A、酸、溶剂混合反应。
进一步地,所述酸选自三氟甲磺酸、对甲苯磺酸、高氯酸、三氟乙酸、樟脑磺酸、五氟苯甲酸、三氟甲磺酸盐、高氯酸盐BBr3中的一种或几种;优选三氟甲磺酸、对甲苯磺酸、三氟乙酸、五氟苯甲酸、樟脑磺酸、三氟甲磺酸铋、三氟甲磺酸锌、三氟甲磺酸铜、三氟甲磺酸铁、高氯酸钴、三溴化铋、高氯酸、三氟甲磺酸盐、高氯酸盐、BBr3中的一种或几种。
进一步地,所述酸的摩尔用量为化合物I摩尔用量的0.01~3倍,优选0.01~2倍。
进一步地,所述第二溶剂选自CF3CH2OH、二氯甲烷、二氯乙烷、氯仿、乙腈、甲苯、DMF中的一种或几种,优选CF3CH2OH、二氯甲烷、甲苯、DMF中的一种或几种,更优选CF3CH2OH和/或二氯甲烷。
进一步地,所述第二溶剂的用量为,化合物I:第二溶剂的料液比为0.3mmol:1~10mL,优选为0.3mmol:2~5mL,更优选为0.3mmol:3mL。
进一步地,加入第二溶剂后的反应温度为20℃~120℃,优选20℃~100℃,更优选20℃~80℃。
进一步地,化合物B选自如下结构:
本发明还提供一种化合物,其具有化合物A或化合物B所示结构:
在本发明中:
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
“元”是表示构成取代基主链的原子个数或构成环的骨架原子的个数。
“烷基”,是指脂肪族烷烃基团,是饱和烃基。其中,烷基可以是直链烷基或支链烷基。典型的烷基包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、已基等等。
本发明中所使用的C1~Cn烷基包括C1~C2、C1~C3......C1~Cn。n是大于或等于一的整数,表示主链上的碳原子数,例如,“C1~C6烷基”是指含有1个至6个碳原子的烷基。
“烯基”,是指具有至少一个碳-碳双键的脂肪族碳氢基团。所述烯基可以是直链或支链的。
“氨基”,是指-NH3。
“酰胺”是具有式-C(O)NHR或-NHC(O)R的化学结构,其中R选自烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基等。
“酰基”是具有式-C(O)R的化学结构,其中R选自烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基等。
“磺酰基”是指具有式-SO2R的化学结构,其中R选自烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基等。
“环”是指任意的共价封闭结构,其中包括如下结构:碳环(如环烷基或芳基)、杂环(如杂环烷基或杂芳基)。环可以是单环、多环或任意取代的环。典型的多环一般有二环、三环(或桥环、螺环)。
“杂烷基”是指含有杂原子的烷基,其中,杂原子包括但不限于N、O、S、P等;氨烷基、硫烷基、烷氧基等都属于杂烷基。
“杂原子”是指除了碳或氢以外的其它原子。杂原子可独立地选自于N、O、S、P或Si,但不限于此。
“芳香基”是指平面环具有离域的π电子系统且含有4n+2个π电子,n为整数。芳香基环可以由五、六、七、八、九或九个以上的原子构成,芳香基包括但不限于噻吩基、苯基、萘基、菲基等等。
“环烷基”是指单环或多环的烃基,其结构式中只含有原子和氢原子,可以是饱和的也可以是不饱和的。
“卤素”是指氟、氯、溴或碘。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
本发明的有益效果是:
(1)本发明方法所使用的原料和试剂原料易得,都可由商业可得的原料方便地制备,成本低廉。
(2)本发明方法所使用的各种原料在常温下可方便地存放,无需严格的特殊处理,可方便管理,且安全性高。
(3)本发明方法的条件温和、操作方便,对底物中的各种官能团的兼容性高,底物适用范围广;反应迅速,制备化合物A的反应仅需1h左右即可反应完全,避免了时间和能源的消耗,合成效率高。
(4)本发明唯一的副产物为水,反应原子经济性高、绿色环保。
(5)本发明化合物A,是一种含有苯并氢化呋喃环、四取代烯烃及膦取代基的多官能团化的化合物,能够发生多种转化,是重要的有机合成中间体,在具有生物活性化合物的合成中具有应用价值。
(6)本发明化合物B,是一种含有苯并呋喃环及膦取代基的多官能团化的化合物,能够发生多种转化,是重要的有机合成中间体,在具有生物活性化合物的合成中具有应用价值。
具体实施方式
以下对本发明的技术方案进行清晰、完整地描述,显然,此处所描述的实施例仅是本发明中的一部分,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例,都属于本发明的保护范围。
本发明实施例中所使用的化合物I可以通过现有技术制备得到(Y.Zhou,X.-P.Xu,S.-J.Ji,Org.Lett.,2019,21,2039.);
化合物II可以商业购买或通过现有技术制备得到(J.Ke,Y.Tang,H.Yi,Y.Li,Y.Cheng,C.Liu,A.Lei,Angew.Chem.,Int.Ed.2015,54,6604.);
实施例中所使用的酸、溶剂等均通过市售购买获得。
本发明系列C3-膦酰基苯并氢化呋喃化合物A的合成通式如下:
实施例1化合物1的合成
在空气氛围下,向5.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二苯甲醇(99.0mg,0.3mmol),二苯基膦氧(66.7mg,0.33mmol),三氟甲磺酸(配成三氟甲磺酸的甲苯溶液),干燥的甲苯2mL,室温搅拌至完全溶解。待充分混合后,加热至60℃,继续搅拌TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(二苯基亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二苯基氧化膦(化合物1),产率为81%;熔点:90-92℃;1H NMR(600MHz,CDCl3):δ=7.63-7.60(m,2H),7.46-7.43(m,4H),7.33-7.28(m,4H),7.27-7.25(m,2H),7.21-7.15(m,4H),7.12-7.10(m,2H),6.91-6.90(m,2H),6.66-6.65(m,1H),6.34-6.33(m,2H),5.54(d,J=15.0Hz,1H),3.70(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=160.9(d,JC-P=3.0Hz),159.7(d,JC-P=4.5Hz),149.4(d,JC-P=10.5Hz),139.7(d,JC-P=3.0Hz),139.2(d,JC-P=4.5Hz),131.72(d,JC-P=3.0Hz),131.66(d,JC-P=3.0Hz),131.6(d,JC-P=6.0Hz),131.5(d,JC-P=7.5Hz),130.4(d,JC-P=96.0Hz),130.3(d,JC-P=1.5Hz),129.74(d,JC-P=3.0Hz),129.71(d,JC-P=96.0Hz),128.6,128.3(d,JC-P=12.0Hz),128.2(d,JC-P=12.0Hz),127.6,126.7(d,JC-P=3.0Hz),125.8(d,JC-P=3.0Hz),120.8(d,JC-P=12.0Hz),113.6(d,JC-P=6.0Hz),107.8(d,JC-P=3.0Hz),96.2,55.4,47.3(d,JC-P=60.0Hz);31P{1H}NMR(243MHz,CDCl3):δ=29.5;HRMS(ESI):Exact mass calcd for C34H27O3P[M+H]+:515.1771,Found:515.1764.
实施例2化合物2的合成
在空气氛围下,向10.0mL的反应管中加入(4,6-二甲氧基苯并呋喃-2-基)二苯基甲醇(108.1mg,0.3mmol),二苯基膦氧(121.3mg,0.6mmol),1.0个当量的对甲苯磺酸一水合物(57.0mg),干燥的1,2-二氯乙烷4mL,室温搅拌至完全溶解。待充分混合后,置于25℃下反应,继续搅拌TLC追踪反应情况,待原料消失完全后。停止反应,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(二苯基亚甲基)-4,6-二甲氧基-2,3-二氢苯并呋喃-3-基)二苯基氧化膦(化合物2),产率为80%;熔点:180-182℃;1H NMR(600MHz,CDCl3):δ=7.54-7.51(m,2H),7.42-7.36(m,4H),7.31-7.28(m,2H),7.28-7.26(m,3H),7.25-7.23(m,3H),7.20-7.17(m,1H),7.13-7.08(m,3H),6.88-6.86(m,2H),6.22(d,J=1.8Hz,1H),5.82(d,J=1.8Hz,1H),5.44(d,J=10.8Hz,1H),3.74(s,3H),3.16(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=162.3,160.3(d,JC-P=4.5Hz),155.9,150.4(d,JC-P=10.5Hz),139.5(d,JC-P=3.0Hz),138.9(d,JC-P=3.0Hz),132.3,131.7(d,JC-P=16.5Hz),131.5(d,JC-P=9.0Hz),131.4(d,JC-P=9.0Hz),131.2(d,JC-P=7.5Hz),130.5,129.7,128.4,127.9(d,JC-P=10.5Hz),127.62,127.55(d,JC-P=12.0Hz),126.7(d,JC-P=30.0Hz),120.8(d,JC-P=12.0Hz),102.3(d,JC-P=7.5Hz),92.4,88.7,55.6,54.6,47.4(d,JC-P=57.0Hz);31P{1H}NMR(243MHz,CDCl3):δ=29.6;HRMS(ESI):Exactmass calcd forC35H29O4P[M+H]+:545.1876,Found:545.1869.
实施例3化合物3的合成
在空气氛围下,向10.0mL的反应管中加入(5-溴-6-甲氧基苯并呋喃-2-基)二苯基甲醇(122.8mg,0.3mmol),二苯基膦氧(151.6mg,0.75mmol),0.1个当量的五氟苯甲酸(6.4mg),干燥的乙腈4mL,室温搅拌至完全溶解。待充分混合后,置于50℃下,继续搅拌TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(5-溴-2-(二苯基亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二苯基氧化膦(化合物3),产率为86%;熔点:184-186℃;1H NMR(600MHz,CDCl3):δ=7.62-7.59(m,2H),7.50-7.46(m,2H),7.45-7.43(m,2H),7.35-7.33(m,2H),7.32-7.29(m,2H),7.27-7.26(m,1H),7.26-7.25(m,1H),7.21-7.19(m,3H),7.17-7.15(m,1H),7.11-7.08(m,2H),6.87-6.85(m,2H),6.71(d,J=2.4Hz,1H),6.42(s,1H),5.51(d,J=13.2Hz,1H),3.78(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=159.1,156.7,149.1(d,JC-P=10.5Hz),139.2(d,JC-P=64.5Hz),131.9(d,JC-P=15.0Hz),131.4(d,JC-P=9.0Hz),130.19(d,JC-P=96.0Hz),130.18,129.8,129.5(d,JC-P=109.5Hz),129.3(d,JC-P=1.5Hz),128.7,128.4(d,JC-P=12.0Hz),128.3(d,JC-P=12.0Hz),127.7,126.9(d,JC-P=10.5Hz),121.4(d,JC-Pp=12.0Hz),114.8(d,JC-P=7.5Hz),103.1,95.1,56.4,47.5(d,JC-P=58.5Hz);31P{1H}NMR(243MHz,CDCl3):δ=29.0;HRMS(ESI):Exact masscalcd forC34H26BrO3P[M+H]+:593.0876,Found:593.0883.
实施例4化合物4的合成
在空气氛围下,向25.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二邻甲苯甲醇(107.5mg,0.3mmol),二苯基膦氧(72.7mg,0.36mmol),0.1个当量的三氟乙酸(配成三氟乙酸的甲苯溶液),干燥的甲苯10mL,室温搅拌至完全溶解。待充分混合后,置于70℃下继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(二-邻甲苯基亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二苯基氧化膦(化合物4),产率为90%;熔点:175-177℃;1H NMR(600MHz,CDCl3):δ=7.53-7.50(m,2H),7.47-7.38(m,5H),7.34-7.31(m,2H),7.26-7.23(m,3H),7.16-7.08(m,4H),6.98-6.83(m,3H),6.39(s,1H),6.19(d,J=7.2Hz,1H),5.73(d,J=312.0Hz,1H),3.68(s,3H),2.31(brs,3H),1.56(brs,3H);13C{1H}NMR(150MHz,CDCl3):δ=160.9,160.1,131.82,131.75,131.3,130.9(d,JC-P=9.0Hz),130.3,130.1,128.3(d,JC-P=12.0Hz),128.2(d,JC-P=12.0Hz),127.5,126.7,125.5(d,JC-P=40.5Hz),124.8,113.4(d,JC-P=6.0Hz),107.6,96.1,55.4,46.4(d,JC-P=64.5Hz),20.5,20.0;31P{1H}NMR(243MHz,CDCl3):δ=28.1;HRMS(ESI):Exact mass calcd for C36H31O3P[M+H]+:543.2084,Found:543.2078.
实施例5化合物5的合成
在空气氛围下,向10.0mL的反应管中加入二(2-氯苯基)(6-甲氧基苯并呋喃-2-基)甲醇(119.8mg,0.3mmol),二苯基膦氧(90.9mg,0.45mmol),2.0个当量的对甲苯磺酸水合物(114.1mg),干燥的乙酸乙酯4mL,室温搅拌至完全溶解。待充分混合后,置于80℃下反应继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(双(2-氯苯基)亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二苯基氧化膦(化合物5),产率为88%;熔点:102-104℃;1HNMR(600MHz,CDCl3):δ=7.67-7.64(m,2H),7.50-7.48(m,1H),7.47-7.42(m,4H),7.35-7.32(m,7H),7.16-7.13(m,4H),6.33(brs,2H),6.29-6.27(m,1H),5.44(d,J=17.4Hz,1H),3.68(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=161.1,159.6(d,JC-P=4.5Hz),133.4,132.2(d,JC-P=7.5Hz),132.0(d,JC-P=10.5Hz),131.5(d,JC-P=9.0Hz),129.8,128.6,128.5,128.4(d,JC-P=3.0Hz),128.3,126.9,126.3,125.8,114.0,108.0,96.3,55.6,48.6(d,JC-P=60.0Hz);31P{1H}NMR(243MHz,CDCl3):δ=29.4;HRMS(ESI):Exactmass calcd for C34H25Cl2O3P[M+H]+:583.0991,Found:583.0989.
实施例6化合物6的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)双(3-甲氧基苯基)甲醇(117.1mg,0.3mmol),二苯基膦氧(181.9mg,0.9mmol),0.1个当量的樟脑磺酸(6.9mg),干燥的四氢呋喃4mL,室温搅拌至完全溶解。待充分混合后,置于60℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(双(3-(甲氧基苯基)亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二苯基氧化膦(化合物6),产率为86%;熔点:172-174℃;1HNMR(600MHz,CDCl3):δ=7.66-7.63(m,2H),7.46-7.42(m,4H),7.34-7.31(m,2H),7.30-7.27(m,2H),7.18-7.16(m,1H),7.11-7.08(m,1H),6.78-6.74(m,3H),6.72-6.68(m,3H),6.35-6.32(m,2H),6.24(s,1H),5.60(d,J=15.6Hz,1H),3.74(s,3H),3.69(s,3H),3.64(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=160.9,159.6(d,JC-P=4.5Hz),159.2(d,JC-P=96.0Hz),149.7(d,JC-P=10.5Hz),140.9,140.4(d,JC-P=4.5Hz),131.7(d,JC-P=13.5Hz),131.6,131.4(d,JC-P=9.0Hz),130.6(d,JC-P=96.0Hz),129.4,129.3(d,JC-P=96.0Hz),128.5,128.2(d,JC-P=12.0Hz),128.0(d,JC-P=10.5Hz),126.0(d,JC-P=1.5Hz),122.4(d,JC-P=6.0Hz),120.4(d,JC-P=10.5Hz),115.8(d,JC-P=54.0Hz),113.5(d,JC-P=7.5Hz),112.5(d,JC-P=90.0Hz),107.8,96.1,55.4,55.2,54.9,47.3(d,JC-P=58.5Hz);31P{1H}NMR(243MHz,CDCl3):δ=29.6;HRMS(ESI):Exact mass calcd forC36H31O5P[M+H]+:575.1982,Found:575.1981.
实施例7化合物7的合成
在空气氛围下,向10.0mL的反应管中加入双(3-氯苯基)(6-甲氧基苯并呋喃-2-基)甲醇(119.8mg,0.3mmol),二苯基膦氧(66.7mg,0.33mmol),0.1个当量的HOTf(配成HOTf的三氯甲烷溶液),干燥的三氯甲烷3mL,室温搅拌至完全溶解。待充分混合后,置于0℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,恢复至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(双(3-氯苯基)亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二苯基氧化膦(化合物7),产率为76%;熔点:234-236℃;1HNMR(600MHz,CDCl3):δ=7.63-7.60(m,2H),7.52-7.46(m,4H),7.36-7.32(m,4H),7.21-7.12(m,5H),7.02-6.98(m,2H),6.69(s,1H),6.58(dd,J=6.0Hz,2.4Hz,1H),6.38-6.37(m,1H),6.34(dd,J=6.0Hz,2.4Hz,1H),5.50(d,J=15.0Hz,1H),3.71(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=161.0,159.4(d,JC-P=4.5Hz),151.2(d,JC-P=9.0Hz),141.1(d,JC-P=3.0Hz),140.4(d,JC-P=3.0Hz),134.1(d,JC-P=126.0Hz),132.1,131.5(d,JC-P=9.0Hz),131.4(d,JC-P=9.0Hz),130.5,130.3,129.85,129.6,129.4(d,JC-P=97.5Hz),129.0,128.3(d,JC-P=13.5Hz),128.2,127.9,127.3(d,JC-P=66.0Hz),125.7(d,JC-P=1.5Hz),118.2(d,JC-P=10.5Hz),113.2(d,JC-P=7.5Hz),108.2,96.2,55.5,47.6(d,JC-P=58.5Hz);31P{1H}NMR(243MHz,CDCl3):δ=29.3;HRMS(ESI):Exact mass calcdfor C34H25Cl2O3P[M+H]+:583.0991,Found:583.0989.
实施例8化合物8的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二对甲苯甲醇(107.5mg,0.3mmol),二苯基膦氧(66.7mg,0.33mmol),三氟甲磺酸铋(19.7mg),干燥三氯甲烷3mL,室温搅拌至完全溶解。待充分混合后,置于30℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(二-对甲苯基亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二苯基氧化膦(化合物8),产率为84%;熔点:232-234℃;1H NMR(600MHz,CDCl3):δ=7.65-7.62(m,2H),7.46-7.42(m,4H),7.33-7.30(m,2H),7.29-7.26(m,2H),7.11-7.06(m,4H),6.88(AB,J=7.8Hz,2H),6.78(AB,J=7.8Hz,2H),6.72-6.71(m,1H),6.35-6.33(m,2H),5.54(d,J=15.0Hz,1H),3.70(s,3H),2.34(s,3H),2.32(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=160.9,159.8,148.7(d,JC-P=10.5Hz),136.6(d,JC-P=37.5Hz),136.2(d,JC-P=52.5Hz),131.6(d,JC-P=7.5Hz),131.4(d,JC-P=9.0Hz),130.7(d,JC-P=96.0Hz),129.8(d,JC-P=73.5Hz),129.6(d,JC-P=96.0Hz),129.4,128.4,128.2(d,JC-P=10.5Hz),128.0(d,JC-P=12.0Hz),120.5(d,JC-P=10.5Hz),113.7(d,JC-P=7.5Hz),107.6,96.1,55.4,47.2(d,JC-P=60.0Hz),21.24,21.18;31P{1H}NMR(243MHz,CDCl3):δ=29.4;HRMS(ESI):Exact mass calcd for C36H31O3P[M+H]+:543.2084,Found:543.2079.
实施例9化合物9的合成
在空气氛围下,向10.0mL的反应管中加入双(4-氯苯基)(6-甲氧基苯并呋喃-2-基)甲醇(119.8mg,0.3mmol),二苯基膦氧(66.7mg,0.33mmol),三氟甲磺酸铋(19.7mg),干燥丙酮3mL,室温搅拌至完全溶解。待充分混合后,置于40℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(双(4-氯苯基)亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二苯基氧化膦(化合物9),产率为83%;熔点:228-230℃;1HNMR(600MHz,CDCl3):δ=7.62-7.58(m,2H),7.51-7.43(m,4H),7.35-7.32(m,4H),7.23-7.21(m,2H),7.12-7.10(m,2H),7.06-7.04(m,2H),6.85-6.83(m,2H),6.55-6.53(m,1H),6.362-6.359(m,1H),6.33-6.31(m,1H),5.45(d,J=14.4Hz,1H),3.70(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=161.0,159.5(d,JC-P=4.5Hz),150.3(d,JC-P=9.0Hz),137.8,137.2(d,JC-P=3.0Hz),132.7(d,JC-P=45.0Hz),131.8,131.5(d,JC-P=12.0Hz),131.2(d,JC-P=52.5Hz),130.2(d,JC-P=96.0Hz),129.7(d,JC-P=96.0Hz),129.0,128.4(d,JC-P=7.5Hz),128.3(d,JC-P=7.5Hz),128.0,125.8(d,JC-P=3.0Hz),118.4(d,JC-P=10.5Hz),113.1(d,JC-P=6.0Hz),108.0,96.2,55.5,47.3(d,JC-P=58.5Hz);31P{1H}NMR(243MHz,CDCl3):δ=29.1;HRMS(ESI):Exact mass calcd for C34H25Cl2O3P[M+H]+:583.0991,Found:583.0991.
实施例10化合物10的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二(萘-2-基)甲醇(129.2mg,0.3mmol),二苯基膦氧(66.7mg,0.3mmol),0.5个当量的三氟甲磺酸铋(98.4mg),干燥的乙醚3mL,室温搅拌至完全溶解。待充分混合后,置于60℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(二(萘-2-基)亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二苯基氧化膦(化合物10),产率为81%;熔点:213-215℃;1H NMR(600MHz,CDCl3):δ=7.81-7.78(m,2H),7.75-7.71(m,3H),7.63-7.60(m,3H),7.57-7.56(m,1H),7.52-7.46(m,2H),7.46-7.39(m,5H),7.36-7.28(m,3H),7.16-7.13(m,2H),7.11-7.08(m,2H),7.06-7.04(m,1H),6.71-6.69(m,1H),6.39-6.36(m,2H),5.74(d,J=14.4Hz,1H),3.71(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=161.0,159.8(d,JC-P=4.5Hz),150.3(d,JC-P=9.0Hz),136.9(d,JC-P=91.5Hz),133.3(d,JC-P=84.0Hz),132.4(d,JC-P=10.5Hz),131.7(d,JC-P=22.5Hz),131.5(d,JC-P=9.0Hz),131.3(d,JC-P=9.0Hz),130.7(d,JC-P=96.0Hz),129.4(d,JC-P=97.5Hz),129.2(d,JC-P=31.5Hz),128.3(d,JC-P=9.0Hz),128.1(d,JC-P=3.0Hz),128.0,127.9(d,JC-P=12.0Hz),127.5(d,JC-P=15.0Hz),127.0,126.0,125.9,120.6(d,JC-P=10.5Hz),113.4(d,JC-P=7.5Hz),107.9,96.1,55.4,47.3(d,JC-P=58.5Hz);31P{1H}NMR(243MHz,CDCl3):δ=29.2;HRMS(ESI):Exact masscalcd for C42H31O3P[M+H]+:615.2084,Found:615.2083.
实施例11化合物11的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二(噻吩-2-基)甲醇(102.7mg,0.3mmol),二苯基膦氧(66.7mg,0.33mmol),0.1个当量的三氟甲磺酸铋(19.7mg),干燥的1,2-二氯乙烷4mL,室温搅拌至完全溶解。待充分混合后,置于70℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(二(噻吩-2-基)亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二苯基氧化膦(化合物11),产率为73%;熔点:168-170℃;1HNMR(600MHz,CDCl3):δ=7.64-7.61(m,2H),7.48-7.43(m,4H),7.36-7.29(m,4H),7.26-7.25(m,1H),7.19-7.18(m,1H),6.97-6.94(m,2H),6.79(dd,J=8.4Hz,2.4Hz,1H),6.76-6.74(m,1H),6.494-6.489(m,1H),6.430-6.426(m,1H),6.39(dd,J=8.4Hz,2.4Hz,1H),5.59(d,J=16.8Hz,1H),3.72(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=161.0,159.1(d,JC-P=4.5Hz),150.1(d,JC-P=10.5Hz),141.4(d,JC-P=6.0Hz),138.4,131.7(d,JC-P=27.0Hz),131.6,131.4(d,JC-P=9.0Hz),130.6(d,JC-P=96.0Hz),129.7,129.0(d,JC-P=97.5Hz),128.4(d,JC-P=12.0Hz),128.2(d,JC-P=10.5Hz),127.6,127.0(d,JC-P=1.5Hz),126.2(d,JC-P=9.0Hz),125.6,125.4,113.8(d,JC-P=7.5Hz),108.2,108.0(d,JC-P=10.5Hz),96.2,55.5,48.5(d,JC-P=58.5Hz);31P{1H}NMR(243MHz,CDCl3):δ=29.3;HRMS(ESI):Exact mass calcd for C30H23O3PS2[M+H]+:527.0899,Found:527.0894.
实施例12化合物12的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并[b]噻吩-2-基)二苯基甲醇(103.9mg,0.3mmol),二苯基膦氧(121.3mg,0.6mmol),2.0个当量的三氟甲磺酸铋(393.7mg),干燥的甲醇4mL,室温搅拌至完全溶解。待充分混合后,置于80℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(二苯基亚甲基)-6-甲氧基-2,3-二氢苯并[b]噻吩-3-基)二苯基氧化膦(化合物12),产率为84%;熔点:68-70℃;1H NMR(600MHz,CDCl3):δ=7.58-7.55(m,2H),7.53-7.48(m,3H),7.42-7.39(m,3H),7.32-7.26(m,5H),7.23-7.21(m,1H),7.20-7.17(m,2H),7.14-7.13(m,2H),6.74-6.73(m,2H),6.66-6.65(m,1H),6.52(dd,J=8.4Hz,2.4Hz,1H),6.40(dd,J=8.4Hz,2.4Hz,1H),5.62(d,J=12.6Hz,1H),3.70(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=159.9,143.9(d,JC-P=3.0Hz),142.0,140.6,138.7(d,JC-P=10.5Hz),134.8(d,JC-P=10.5Hz),132.1(d,JC-P=7.5Hz),131.8(d,JC-P=15.0Hz),131.6(d,JC-P=13.5Hz),131.2(d,JC-P=96.0Hz),129.8,129.7(d,JC-P=93.0Hz),129.0(d,JC-P=1.5Hz),128.5,128.3(d,JC-P=10.5Hz),128.2(d,JC-P=10.5Hz),128.0,127.8,127.0,125.5,124.7(d,JC-P=7.5Hz),110.4,107.5,55.4,55.3(d,JC-P=55.5Hz);31P{1H}NMR(243MHz,CDCl3):δ=31.9;HRMS(ESI):Exactmass calcdfor C34H27O2PS[M+H]+:531.1542,Found:531.1540.
实施例13化合物13的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二苯甲醇(99.0mg,0.3mmol),二邻甲苯基氧化膦(76.0mg,0.33mmol),0.1个当量的三氟甲磺酸锌(10.9mg),干燥的DMF3mL,室温搅拌至完全溶解。待充分混合后,置于100℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,将反应液转入分液漏斗,加入30mL水,用乙酸乙酯简单的萃取三次后,合并有机相,并用无水硫酸钠干燥。向干燥后的有机相中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(二苯基亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二邻甲苯基氧化膦(化合物13),产率为91%;熔点:161-163℃;1H NMR(600MHz,CDCl3):δ=7.37-7.33(m,1H),7.31-7.28(m,2H),7.27-7.24(m,2H),7.23-7.17(m,4H),7.16-7.11(m,3H),7.08-7.02(m,4H),6.93-6.91(m,3H),6.45-6.44(m,1H),6.38(dd,J=9.0Hz,2.4Hz,1H),5.70(d,J=11.4Hz,1H),3.71(s,3H),2.22(s,3H),2.16(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=160.9(d,JC-P=1.5Hz),160.2(d,JC-P=4.5Hz),150.2(d,JC-P=10.5Hz),144.0(d,JC-P=6.0Hz),143.3(d,JC-P=7.5Hz),139.7(d,JC-P=3.0Hz),139.2(d,JC-P=4.5Hz),132.4(d,JC-P=10.5Hz),132.3(d,JC-P=9.0Hz),132.0(d,JC-P=10.5Hz),131.7(d,JC-P=12.0Hz),131.43(d,JC-P=3.0Hz),131.39(d,JC-P=3.0Hz),130.5(d,JC-P=1.5Hz),130.0(d,JC-P=93.0Hz),129.8(d,JC-P=1.5Hz),129.4(d,JC-P=93.0Hz),128.7,127.6,126.8(d,JC-P=34.5Hz),126.1(d,JC-P=4.5Hz),125.0(d,JC-P=12.0Hz),124.6(d,JC-P=12.0Hz),121.1(d,JC-P=10.5Hz),114.0(d,JC-P=6.0Hz),107.9(d,JC-P=1.5Hz),96.3(d,JC-P=1.5Hz),55.5,46.6(d,JC-P=57.0Hz),21.6(d,JC-P=3.0Hz),21.3(d,JC-P=3.0Hz);31P{1H}NMR(243MHz,CDCl3):δ=36.0;HRMS(ESI):Exact mass calcd forC36H31O3P[M+H]+:543.2084,Found:543.2078.
实施例14化合物14的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二苯甲醇(99.0mg,0.3mmol),二间甲苯基氧化膦(76.0mg,0.33mmol),0.1个当量的三氟甲磺酸铜(10.8mg),干燥的甲苯3mL,室温搅拌至完全溶解。待充分混合后,置于60℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(二苯基亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二间甲苯基氧化膦(化合物14),产率为80%;熔点:64-66℃;1H NMR(600MHz,CDCl3):δ=7.44-7.40(m,2H),7.28-7.26(m,2H),7.25-7.23(m,3H),7.22-7.20(m,4H),7.19-7.18(m,2H),7.16-7.13(m,1H),7.10-7.08(m,2H),6.89-6.88(m,2H),6.71-6.69(m,1H),6.35-6.34(m,2H),5.51(d,J=15.0Hz,1H),3.70(s,3H),2.29(s,3H),2.27(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=160.8,159.7(d,JC-P=4.5Hz),149.6(d,JC-P=10.5Hz),139.5(d,JC-P=3.0Hz),139.2(d,JC-P=4.5Hz),138.2(d,JC-P=10.5Hz),137.8(d,JC-P=10.5Hz),132.6,132.3(d,JC-P=7.5Hz),132.1(d,JC-P=7.5Hz),130.3,130.2(d,JC-P=96.0Hz),129.7,129.5(d,JC-P=97.5Hz),128.6(d,JC-P=9.0Hz),128.42,128.37,128.03(d,JC-P=9.0Hz),127.95(d,JC-P=9.0Hz),127.6,126.7,126.6,125.8(d,JC-P=3.0Hz),120.6(d,JC-P=12.0Hz),113.8(d,JC-P=7.5Hz),107.7,96.1,55.4,47.4(d,JC-P=58.5Hz),21.4;31P{1H}NMR(243MHz,CDCl3):δ=30.2;HRMS(ESI):Exact mass calcdfor C36H31O3P[M+H]+:543.2084,Found:543.2081.
实施例15化合物15的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二苯甲醇(99.0mg,0.3mmol),双(4-氯苯基)氧化膦(89.5mg,0.33mmol),0.1个当量的三氟甲磺酸铁(15.1mg),干燥的甲苯3mL,室温搅拌至完全溶解。待充分混合后,置于80℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为双(4-氯苯基)(2-(二苯基亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)氧化膦(化合物15),产率为87%,熔点:204-206℃;1H NMR(600MHz,CDCl3):δ=7.57-7.54(m,2H),7.37-7.34(m,2H),7.30-7.28(m,3H),7.27-7.22(m,4H),7.21-7.18(m,3H),7.15-7.13(m,2H),6.87-6.86(m,2H),6.80-6.78(m,1H),6.39-6.36(m,2H),5.55(d,J=15.6Hz,1H),3.70(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=161.2(d,JC-P=3.0Hz),159.6(d,JC-P=4.5Hz),148.8(d,JC-P=10.5Hz),139.6(d,JC-P=4.5Hz),139.0(d,JC-P=4.5Hz),138.7(d,JC-P=4.5Hz),138.6(d,JC-P=3.0Hz),132.8(d,JC-P=9.0Hz),132.6(d,JC-P=10.5Hz),130.2(d,JC-P=1.5Hz),129.7(d,JC-P=3.0Hz),129.2,128.8(d,JC-P=12.0Hz),128.7,128.6,127.83,127.78,127.2,126.9(d,JC-P=16.5Hz),125.9(d,JC-P=3.0Hz),121.1(d,JC-P=12.0Hz),112.9(d,JC-P=7.5Hz),108.1(d,JC-P=3.0Hz),96.3(d,JC-P=1.5Hz),55.5,47.3(d,JC-P=61.5Hz);31P{1H}NMR(243MHz,CDCl3):δ=27.3;HRMS(ESI):Exact mass calcd for C34H25Cl2O3P[M+H]+:583.0991,Found:583.0993.
实施例16化合物16的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二苯甲醇(99.0mg,0.3mmol),二(2-萘基-)氧化膦(99.7mg,0.33mmol),0.1个当量的六水高氯酸钴(11.0mg),干燥的甲苯3mL,室温搅拌至完全溶解。待充分混合后,置于60℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(二苯基亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)二(2-萘基-)氧化膦(化合物16),产率为85%,熔点:118-120℃;1H NMR(600MHz,CDCl3):δ=8.27-8.24(m,1H),8.16-8.14(m,1H),7.85-7.84(m,2H),7.81-7.79(m,1H),7.78-7.76(m,3H),7.75-7.72(m,1H),7.60-7.57(m,2H),7.53-7.49(m,3H),7.25-7.22(m,4H),7.20-7.15(m,1H),6.91-6.88(m,1H),6.78-6.74(m,5H),6.341-6.338(m,1H),6.30-6.29(m,1H),5.76(d,J=15.0Hz,1H),3.65(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=161.0(d,JC-P=3.0Hz),159.8(d,JC-P=4.5Hz),149.5(d,JC-P=10.5Hz),139.4(d,JC-P=4.5Hz),139.2(d,JC-P=4.5Hz),134.6(d,JC-P=4.5Hz),134.0(d,JC-P=7.5Hz),130.1(d,JC-P=1.5Hz),129.8(d,JC-P=3.0Hz),129.0(d,JC-P=10.5Hz),128.3(d,JC-P=7.5Hz),128.2(d,JC-P=3.0Hz),128.1(d,JC-P=10.5Hz),127.9(d,JC-P=10.5Hz),127.7,127.5,126.83,126.76,126.6(d,JC-P=10.5Hz),126.1(d,JC-P=10.5Hz),126.0(d,JC-P=10.5Hz),125.8(d,JC-P=3.0Hz),120.9(d,JC-P=10.5Hz),113.6(d,JC-P=7.5Hz),108.0,96.3(d,JC-P=1.5Hz),55.4,47.5(d,JC-P=58.5Hz);31P{1H}NMR(243MHz,CDCl3):δ=29.1;HRMS(ESI):Exact mass calcd for C42H31O3P[M+H]+:615.2084,Found:615.2076.
实施例17化合物17的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二苯甲醇(99.0mg,0.3mmol),二(2-噻吩基-)氧化膦(70.7mg,0.33mmol),0.1个当量的三溴化铋(13.5mg),干燥的甲苯3mL,室温搅拌至完全溶解。待充分混合后,置于60℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为(2-(二苯基亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)(噻吩-2-基)(噻吩-3-基)氧化膦(化合物17),产率为40%,熔点:204-206℃;1H NMR(600MHz,CDCl3):δ=7.67-7.65(m,1H),7.61-7.60(m,1H),7.49-7.48(m,1H),7.29-7.27(m,1H),7.261-7.255(m,1H),7.24-7.20(m,4H),7.18-7.16(m,3H),7.10-7.09(m,1H),7.02-6.99(m,3H),6.88-6.86(m,1H),6.43(dd,J=8.4Hz,2.4Hz,1H),6.330-6.326(m,1H),5.48(d,J=19.2Hz,1H),3.71(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=161.2(d,JC-P=3.0Hz),159.8(d,JC-P=4.5Hz),148.7(d,JC-P=12.0Hz),139.6(d,JC-P=4.5Hz),139.2(d,JC-P=6.0Hz),136.4(d,JC-P=10.5Hz),136.2(d,JC-P=9.0Hz),133.98(d,JC-P=4.5Hz),133.96(d,JC-P=4.5Hz),131.0(d,JC-P=61.5Hz),130.32(d,JC-P=3.0Hz),130.27(JC-P=63.0Hz),129.8(d,JC-P=3.0Hz),128.6,128.5(d,JC-P=13.5Hz),128.0(d,JC-P=15.0Hz),127.7,126.8(d,JC-P=24.0Hz),126.1(d,JC-P=3.0Hz),121.8(d,JC-P=13.5Hz),113.3(d,JC-P=7.5Hz),107.9(d,JC-P=3.0Hz),96.2(d,JC-P=3.0Hz),55.5,50.0(d,JC-P=69.0Hz);31P{1H}NMR(243MHz,CDCl3):δ=18.9;HRMS(ESI):Exact masscalcd for C30H23O3PS2[M+H]+:527.0899,Found:527.0893.
实施例18化合物18的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二苯甲醇(99.0mg,0.3mmol),二苄基氧化膦(75.9mg,0.33mmol),0.1个当量的三氟甲磺酸铋(19.7mg),干燥的甲苯3mL,室温搅拌至完全溶解。待充分混合后,置于60℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,冷却至室温,向反应管中加入粗硅胶,旋干后柱层析,淋洗剂为石油醚/乙酸乙酯=1/1,得白色固体产物为二苄基(2-(二苯基亚甲基)-6-甲氧基-2,3-二氢苯并呋喃-3-基)氧化膦(化合物18),产率为63%,熔点:54-56℃;1H NMR(600MHz,CDCl3):δ=7.70-7.66(m,4H),7.54-7.51(m,2H),7.42-7.39(m,4H),7.25-7.19(m,10H),7.00(s,1H),6.66-6.61(m,2H),6.29(s,1H),3.76(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=165.4(d,JC-P=16.5Hz),157.9,155.6(d,JC-P=12.0Hz),140.7,132.9(d,JC-P=108.0Hz),132.1,131.7(d,JC-P=10.5Hz),129.1,128.6(d,JC-P=13.5Hz),128.2,126.6,121.4,121.2(d,JC-P=10.5Hz),112.4,107.1(d,JC-P=118.5Hz),96.0,55.6,48.8;31P{1H}NMR(243MHz,CDCl3):δ=22.0;HRMS(ESI):Exact mass calcd for C34H27O3P[M+H]+:515.1771,Found:515.1768.
本发明系列C3-膦酰基苯并氢化呋喃化合物B的合成通式如下:
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二苯甲醇(99.0mg,0.3mmol),二苯基膦氧(66.7mg,0.33mmol),三氟甲磺酸(配成三氟甲磺酸的甲苯溶液),干燥的甲苯2mL,室温搅拌至完全溶解。待充分混合后,加热至60℃℃,继续搅拌TLC追踪反应情况,待原料消失完全后。停止反应,真空除去甲苯,并向反应管中加入3.0mL三氟乙醇后置于80℃下继续反应48小时。停止反应,经柱层析,淋洗剂为石油醚/乙酸乙酯=2/1,得白色固体产物为(2-苯甲酰基-6-甲氧基苯并呋喃-3-基)二苯基氧化膦(化合物19),产率为78%;熔点:90-92℃;1H NMR(600MHz,CDCl3):δ=7.63-7.60(m,2H),7.46-7.43(m,4H),7.33-7.28(m,4H),7.27-7.25(m,2H),7.21-7.15(m,4H),7.12-7.10(m,2H),6.91-6.90(m,2H),6.66-6.65(m,1H),6.34-6.33(m,2H),5.54(d,J=15.0Hz,1H),3.70(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=160.9(d,JC-P=3.0Hz),159.7(d,JC-P=4.5Hz),149.4(d,JC-P=10.5Hz),139.7(d,JC-P=3.0Hz),139.2(d,JC-P=4.5Hz),131.72(d,JC-P=3.0Hz),131.66(d,JC-P=3.0Hz),131.6(d,JC-P=6.0Hz),131.5(d,JC-P=7.5Hz),130.4(d,JC-P=96.0Hz),130.3(d,JC-P=1.5Hz),129.74(d,JC-P=3.0Hz),129.71(d,JC-P=96.0Hz),128.6,128.3(d,JC-P=12.0Hz),128.2(d,JC-P=12.0Hz),127.6,126.7(d,JC-P=3.0Hz),125.8(d,JC-P=3.0Hz),120.8(d,JC-P=12.0Hz),113.6(d,JC-P=6.0Hz),107.8(d,JC-P=3.0Hz),96.2,55.4,47.3(d,JC-P=60.0Hz);31P{1H}NMR(243MHz,CDCl3):δ=29.5;HRMS(ESI):Exact masscalcd for C34H27O3P[M+H]+:515.1771,Found:515.1764.
实施例20化合物20的合成
在空气氛围下,向10.0mL的反应管中加入(4,6-二甲氧基苯并呋喃-2-基)二苯基甲醇(108.1mg,0.3mmol),二苯基膦氧(121.3mg,0.6mmol),1.0个当量的对甲苯磺酸一水合物(57.0mg),干燥的1,2-二氯乙烷4mL,室温搅拌至完全溶解。待充分混合后,置于25℃下反应,继续搅拌TLC追踪反应情况,待原料消失完全后。停止反应,真空除去1,2-二氯乙烷,并向反应管中加入3.0mL三氟乙醇后置于80℃下继续反应48小时。停止反应,经柱层析,淋洗剂为石油醚/乙酸乙酯=2/1,得白色固体产物为(2-苯甲酰基-4,6-二甲氧基苯并呋喃-3-基)二苯基氧化膦(化合物20),产率为76%;熔点:224-226℃;1H NMR(600MHz,CDCl3):δ=7.71-7.67(m,4H),7.48-7.45(m,2H),7.39-7.36(m,4H),7.30-7.28(m,4H),7.27-7.24(m,4H),7.21-7.19(m,2H),6.88(s,1H),6.65-6.64(m,1H),6.13(d,J=2.4Hz,1H),3.77(s,3H),3.12(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=165.5(d,JC-P=16.5Hz),159.3,156.4(d,JC-P=10.5Hz),153.1,141.5,134.4(d,JC-P=111.0Hz),131.5(d,JC-P=10.5Hz),131.3,129.2,128.2,128.0(d,JC-P=13.5Hz),126.5,111.3(d,JC-P=9.0Hz),105.5(d,JC-P=115.5Hz),95.0,88.4,55.7,54.2,48.2;31P{1H}NMR(243MHz,CDCl3):δ=25.4;HRMS(ESI):Exact mass calcd for C33H29O4P[M+H]+:545.1876,Found:545.1880.
实施例21化合物21的合成
在空气氛围下,向25.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二邻甲苯甲醇(107.5mg,0.3mmol),二苯基膦氧(72.7mg,0.36mmol),0.1个当量的三氟乙酸(配成三氟乙酸的甲苯溶液),干燥的甲苯10mL,室温搅拌至完全溶解。待充分混合后,置于70℃下继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,真空除去甲苯,并向反应管中加入3.0mL三氟乙醇后置于80℃下继续反应24小时。停止反应,经柱层析,淋洗剂为石油醚/乙酸乙酯=2/1,得白色固体产物为(2-(二-邻甲苯基甲基)-6-甲氧基苯并呋喃-3-基)二苯基氧化膦(化合物21),产率为85%;熔点:210-212℃;1H NMR(600MHz,CDCl3):δ=7.60-7.57(m,4H),7.49-7.46(m,2H),7.35-7.32(m,4H),7.14-7.09(m,4H),7.06-7.03(m,2H),6.993-6.991(m,1H),6.93-6.92(m,2H),6.68-6.66(m,1H),6.62-6.60(m,2H),3.76(s,3H),2.16(s,6H);13C{1H}NMR(150MHz,CDCl3):δ=165.5(d,JC-P=18.0Hz),157.8,155.4(d,JC-P=12.0Hz),139.2,136.8,132.7(d,JC-P=109.5Hz),131.9,131.5(d,JC-P=10.5Hz),130.2,128.8,128.4(d,JC-P=13.5Hz),126.7,125.6,121.4,121.3,112.6,106.0(d,JC-P=117.0Hz),96.0,55.6,43.9,19.7;31P{1H}NMR(243MHz,CDCl3):δ=21.2;HRMS(ESI):Exactmass calcd forC36H31O3P[M+H]+:543.2084,Found:543.2089.
实施例22化合物22的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)双(3-甲氧基苯基)甲醇(117.1mg,0.3mmol),二苯基膦氧(181.9mg,0.9mmol),0.1个当量的樟脑磺酸(6.9mg),干燥的四氢呋喃4mL,室温搅拌至完全溶解。待充分混合后,置于60℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,真空除去四氢呋喃,并向反应管中加入3.0mL三氟乙醇后置于80℃下继续反应24小时。停止反应,经柱层析,淋洗剂为石油醚/乙酸乙酯=2/1,得白色固体产物为(2-(双(3-甲氧基苯基)甲基)-6-甲氧基苯并呋喃-3-基)二苯基氧化膦(化合物22),产率为85%;熔点:79-81℃;1H NMR(600MHz,CDCl3):δ=7.70-7.67(m,4H),7.54-7.52(m,2H),7.43-7.40(m,4H),7.15(t,J=7.8Hz,2H),7.014-7.009(m,1H),6.82-6.81(m,2H),6.77-6.76(m,2H),6.75-6.73(m,2H),6.66-6.64(m,1H),6.61-6.60(m,1H),6.26(s,1H),3.77(s,3H),3.69(s,6H);13C{1H}NMR(150MHz,CDCl3):δ=165.2(d,JC-P=18.0Hz),159.4,158.0,155.6(d,JC-P=10.5Hz),142.0,132.9(d,JC-P=108.0Hz),132.1,131.7(d,JC-P=10.5Hz),129.2,128.6(d,JC-P=12.0Hz),121.5,121.4,121.2(d,JC-P=9.0Hz),114.9,112.5,112.1,107.1(d,JC-P=117.0Hz),96.0,55.6,55.1,48.8;31P{1H}NMR(243MHz,CDCl3):δ=22.1;HRMS(ESI):Exact mass calcd for C36H31O5P[M+H]+:575.1982,Found:575.1985.
实施例23化合物23的合成
在空气氛围下,向10.0mL的反应管中加入双(4-氯苯基)(6-甲氧基苯并呋喃-2-基)甲醇(119.8mg,0.3mmol),二苯基膦氧(66.7mg,0.33mmol),三氟甲磺酸铋(19.7mg),干燥丙酮3mL,室温搅拌至完全溶解。待充分混合后,置于40℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,真空除去丙酮,并向反应管中加入3.0mL三氟乙醇后置于80℃下继续反应72小时。停止反应,经柱层析,淋洗剂为石油醚/乙酸乙酯=2/1,得白色固体产物为(2-(双(4-氯苯基)甲基)-6-甲氧基苯并呋喃-3-基)二苯基氧化膦(化合物23),产率为85%;熔点:132-134℃;1H NMR(600MHz,CDCl3):δ=7.69-7.65(m,4H),7.57-7.54(m,2H),7.44-7.41(m,4H),7.21(AB,J=8.4Hz,4H),7.14(AB,J=8.4Hz,4H),7.00(t,J=1.8Hz,1H),6.66(dd,J=8.4Hz,2.4Hz,1H),6.50-6.47(m,2H),3.78(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=164.5(d,JC-P=18.0Hz),158.1,155.6(d,JC-P=12.0Hz),138.8,133.0,132.7,132.3(d,JC-P=1.5Hz),131.6(d,JC-P=10.5Hz),130.3,128.7(d,JC-P=12.0Hz),128.5,121.3,120.8(d,JC-P=10.5Hz),112.7,107.6(d,JC-P=115.5Hz),96.0,55.6,47.6;31P{1H}NMR(243MHz,CDCl3):δ=21.5;HRMS(ESI):Exact masscalcd forC34H25Cl2O3P[M+H]+:583.0991,Found:583.0993.
实施例24化合物24的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二(噻吩-2-基)甲醇(102.7mg,0.3mmol),二苯基膦氧(66.7mg,0.33mmol),0.1个当量的三氟甲磺酸铋(19.7mg),干燥的1,2-二氯乙烷4mL,室温搅拌至完全溶解。待充分混合后,置于70℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,真空除去1,2-二氯乙烷,并向反应管中加入3.0mL三氟乙醇后置于80℃下继续反应24小时。停止反应,经柱层析,淋洗剂为石油醚/乙酸乙酯=2/1,得白色固体产物为(2-(二(噻吩-2-基)甲基)-6-甲氧基苯并呋喃-3-基)二苯基氧化膦(化合物24),产率为73%;熔点:119-121℃;1H NMR(400MHz,CDCl3):δ=7.74-7.71(m,4H),7.57-7.55(m,2H),7.47-7.44(m,4H),7.18(dd,J=4.8Hz,1.2Hz,2H),7.06(d,J=1.8Hz,1H),6.96-6.95(m,2H),6.90-6.89(m,2H),6.82(s,1H),6.67(d,J=2.4Hz,2H),3.78(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=163.5(d,JC-P=18.0Hz),158.2,155.5(d,JC-P=12.0Hz),143.1,132.6(d,JC-P=109.5Hz),132.3(d,JC-P=1.5Hz),131.7(d,JC-P=10.5Hz),128.7(d,JC-P=12.0Hz),126.5(d,JC-P=10.5Hz),125.0,121.6,120.9(d,JC-P=10.5Hz),112.8,106.3(d,JC-P=117.0Hz),96.0,55.6,39.7;31P{1H}NMR(243MHz,CDCl3):δ=21.4;HRMS(ESI):Exact mass calcd forC30H23O3PS2[M+H]+:527.0899,Found:527.0904.
实施例25化合物25的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二(萘-2-基)甲醇(129.2mg,0.3mmol),二苯基膦氧(66.7mg,0.3mmol),0.5个当量的三氟甲磺酸铋(98.4mg),干燥的乙醚3mL,室温搅拌至完全溶解。待充分混合后,置于60℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,真空除去乙醚,并向反应管中加入3.0mL三氟乙醇后置于80℃下继续反应24小时。停止反应,经柱层析,淋洗剂为石油醚/乙酸乙酯=2/1,得白色固体产物为(2-(二(萘-2-基)甲基)-6-甲氧基苯并呋喃-3-基)二苯基氧化膦(化合物25),产率为80%;熔点:196-198℃;1H NMR(600MHz,CDCl3):δ=7.81-7.79(m,2H),7.74-7.72(m,5H),7.70-7.68(m,3H),7.63(s,2H),7.52-7.49(m,2H),7.46-7.40(m,6H),7.39-7.36(m,4H),7.04-7.03(m,1H),6.69-6.68(m,2H),6.64-6.62(m,1H),3.78(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=165.3(d,JC-P=18.0Hz),158.0,155.7(d,JC-P=12.0Hz),138.1,133.3,132.8(d,JC-P=108.0Hz),132.3,132.2(d,JC-P=3.0Hz),131.7(d,JC-P=10.5Hz),128.6(d,JC-P=13.5Hz),127.9,127.8,127.5(d,JC-P=1.5Hz),125.8(d,JC-P=25.5Hz),121.4,121.2(d,JC-P=10.5Hz),112.6,107.4(d,JC-P=117.0Hz),96.0,55.6,49.2;31P{1H}NMR(243MHz,CDCl3):δ=21.5;HRMS(ESI):Exact mass calcd for C42H31O3P[M+H]+:615.2084,Found:615.2084.
实施例26化合物26的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二苯甲醇(99.0mg,0.3mmol),二邻甲苯基氧化膦(76.0mg,0.33mmol),0.1个当量的三氟甲磺酸锌(10.9mg),干燥的DMF 3mL,室温搅拌至完全溶解。待充分混合后,置于100℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,真空除去DMF,并向反应管中加入3.0mL三氟乙醇后置于80℃下继续反应2小时。停止反应,经柱层析,淋洗剂为石油醚/乙酸乙酯=2/1,得白色固体产物为(2-苯甲酰基-6-甲氧基苯并呋喃-3-基)二邻甲苯基氧化膦(化合物26),产率为90%;熔点:80-82℃;1H NMR(600MHz,CDCl3):δ=7.42-7.40(m,2H),7.26-7.10(m,16H),7.04(s,1H),6.59-6.58(m,1H),6.53(s,1H),6.46-6.44(m,1H),3.78(s,3H),2.52(brs,6H);13C{1H}NMR(150MHz,CDCl3):δ=165.4(d,JC-P=18.0Hz),157.9,155.6(d,JC-P=12.0Hz),143.7(d,JC-P=7.5Hz),140.7,132.0(d,JC-P=10.5Hz),129.2,128.2,126.6,125.5(d,JC-P=12.0Hz),121.4(d,JC-P=10.5Hz),121.1,112.4,106.8(d,JC-P=117.0Hz),96.0,55.6,48.8,21.6;31P{1H}NMR(243MHz,CDCl3):δ=28.3;HRMS(ESI):Exact masscalcd for C36H31O3P[M+H]+:543.2084,Found:543.2088.
实施例27化合物27的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二苯甲醇(99.0mg,0.3mmol),二间甲苯基氧化膦(76.0mg,0.33mmol),0.1个当量的三氟甲磺酸铜(10.8mg),干燥的甲苯3mL,室温搅拌至完全溶解。待充分混合后,置于60℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,真空除去甲苯,并向反应管中加入3.0mL三氟乙醇后置于80℃下继续反应12小时。停止反应,经柱层析,淋洗剂为石油醚/乙酸乙酯=2/1,得白色固体产物为(2-苯甲酰基-6-甲氧基苯并呋喃-3-基)二间甲苯基氧化膦(化合物27),产率为78%;熔点:77-79℃;1H NMR(600MHz,CDCl3):δ=7.57-7.55(m,2H),7.44-7.41(m,2H),7.34-7.32(m,2H),7.31-7.28(m,2H),7.25-7.23(m,4H),7.21-7.19(m,2H),7.17-7.16(m,4H),7.02-7.01(m,1H),6.80-6.79(m,1H),6.69-6.68(m,1H),6.01(s,1H),3.78(s,3H),2.27(s,6H);13C{1H}NMR(150MHz,CDCl3):δ=164.5(d,JC-P=18.0Hz),157.9,155.6(d,JC-P=12.0Hz),140.7,138.6(d,JC-P=12.0Hz),132.9,132.7(d,JC-P=108.0Hz),132.2(d,JC-P=9.0Hz),129.0,128.7(d,JC-P=10.5Hz),128.4(d,JC-P=13.5Hz),128.2,126.6,121.8,121.4(d,JC-P=10.5Hz),112.4,107.6(d,JC-P=117.0Hz),96.0,55.6,48.9,21.3;31P{1H}NMR(243MHz,CDCl3):δ=22.3;HRMS(ESI):Exact masscalcd forC36H31O3P[M+H]+:543.2084,Found:543.2089.
实施例28化合物28的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二苯甲醇(99.0mg,0.3mmol),双(4-氯苯基)氧化膦(89.5mg,0.33mmol),0.1个当量的三氟甲磺酸铁(15.1mg),干燥的甲苯3mL,室温搅拌至完全溶解。待充分混合后,置于80℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,真空除去甲苯,并向反应管中加入3.0mL三氟乙醇后置于80℃下继续反应48小时。停止反应,经柱层析,淋洗剂为石油醚/乙酸乙酯=2/1,得白色固体产物为(2-二苯甲基-6-甲氧基苯并呋喃-3-基)双(4-氯苯基)氧化膦(化合物28),产率为50%;熔点:81-83℃;1H NMR(600MHz,CDCl3):δ=7.60-7.56(m,4H),7.39-7.37(m,4H),7.26-7.18(m,10H),7.02(t,J=1.8Hz,1H),6.69(dd,J=9.0Hz,2.4Hz,1H),6.58(d,J=9.0Hz,1H),6.34(s,1H),3.78(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=166.1(d,JC-P=19.5Hz),158.1,155.7(d,JC-P=13.5Hz),140.4,139.0,133.0(d,JC-P=12.0Hz),131.1(d,JC-P=109.5Hz),129.1(d,JC-P=13.5Hz),129.0,128.4,126.8,121.0,120.7(d,JC-P=10.5Hz),112.8,106.2(d,JC-P=120.0Hz),96.2,55.7,49.0;31P{1H}NMR(243MHz,CDCl3):δ=20.5;HRMS(ESI):Exact mass calcd for C34H25Cl2O3P[M+H]+:583.0991,Found:583.0994.
实施例29化合物29的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并呋喃-2-基)二苯甲醇(99.0mg,0.3mmol),二(2-萘基-)氧化膦(99.7mg,0.33mmol),0.1个当量的六水高氯酸钴(11.0mg),干燥的甲苯3mL,室温搅拌至完全溶解。待充分混合后,置于60℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,真空除去甲苯,并向反应管中加入3.0mL三氟乙醇后置于80℃下继续反应24小时。停止反应,经柱层析,淋洗剂为石油醚/乙酸乙酯=2/1,得白色固体产物为(2-二苯甲基-6-甲氧基苯并呋喃-3-基)二(萘-2-基)氧化膦(化合物29),产率为83%;熔点:184-186℃;1H NMR(600MHz,CDCl3):δ=8.29-8.27(m,2H),7.88-7.87(m,4H),7.77-7.73(m,4H),7.61-7.59(m,2H),7.54-7.51(m,2H),7.19-7.14(m,10H),7.04(s,1H),6.76(d,J=8.4Hz,1H),6.61(dd,J=8.4Hz,2.4Hz,1H),6.25(s,1H),3.76(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=165.3(d,JC-P=19.5Hz),158.0,155.7(d,JC-P=12.0Hz),140.6,134.8,133.7(d,JC-P=10.5Hz),132.5(d,JC-P=13.5Hz),130.1(d,JC-P=108.0Hz),129.0(d,JC-P=7.5Hz),128.6(d,JC-P=12.0Hz),128.3(d,JC-P=6.0Hz),127.8,126.8(d,JC-P=30.0Hz),126.6(d,JC-P=10.5Hz),121.6,121.3(d,JC-P=10.5Hz),112.5,107.2(d,JC-P=117.0Hz),96.1,55.6,49.1;31P{1H}NMR(243MHz,CDCl3):δ=22.2;HRMS(ESI):Exact mass calcd for C42H31O3P[M+H]+:615.2084,Found:615.2084.
实施例30化合物30的合成
在空气氛围下,向10.0mL的反应管中加入(6-甲氧基苯并[b]噻吩-2-基)二苯基甲醇(103.9mg,0.3mmol),二苯基膦氧(121.3mg,0.6mmol),2.0个当量的三氟甲磺酸铋(393.7mg),干燥的甲醇4mL,室温搅拌至完全溶解。待充分混合后,置于80℃下,继续搅拌通过TLC追踪反应情况,待原料消失完全后。停止反应,真空除去甲醇,并向反应管中加入3.0mL三氟乙醇后置于80℃下继续反应22小时。停止反应,经柱层析,淋洗剂为石油醚/乙酸乙酯=2/1,得白色固体产物为(2-苯甲酰基-6-甲氧基苯并[b]噻吩-3-基)二苯基氧化膦(化合物30),产率为68%;熔点:65-67℃;1H NMR(600MHz,CDCl3):δ=7.57-7.54(m,4H),7.49-7.47(m,2H),7.36-7.33(m,4H),7.22-7.18(m,8H),7.11-7.10(m,4H),6.74(s,1H),6.73-6.71(m,1H),3.77(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=160.3(d,JC-P=12.0Hz),157.1,143.4,140.9(d,JC-P=13.5Hz),134.4(d,JC-P=15.0Hz),133.2(d,JC-P=105.0Hz),132.0,131.8(d,JC-P=9.0Hz),129.4,128.6(d,JC-P=12.0Hz),128.2,126.8,125.5,121.8(d,JC-P=102.0Hz),114.3,104.5,55.6,49.8;31P{1H}NMR(243MHz,CDCl3):δ=24.6;HRMS(ESI):Exact mass calcd for C34H27O2PS[M+H]+:531.1542,Found:531.1546.
通过以上方法所获得的C3-膦酰基苯并氢化呋喃和C3-膦酰基苯并呋喃可以进行进一步结构修饰,作为药物或其他有机化合物的重要合成砌块。在此对其使用效果的实施方式进行具体陈述,但需将强调的是本发明决不仅限于这几个实施示例所表示内容。
实施例31化合物31的合成
氮气氛围下,向25.0mL干燥的三颈瓶中依次加入化合物1(514mg,1.0mmol),2.0mmol的BBr3(0.2mL),6mL二氯甲烷,置于-78℃搅拌反应0.5小时后,后于25℃下继续反应,通过TLC监测反应进程,待反应结束后,将反应液倒入装有碎冰的烧杯中,并用饱和碳酸氢钠溶液调节pH至弱碱性,随后用二氯甲烷萃取三次,合并有机相并用无水硫酸钠干燥。真空除去多余溶剂后经柱层析,淋洗剂为二氯甲烷/甲醇=30/1,得到粉色固体31,产率为80%。熔点:224-226℃;1H NMR(600MHz,DMSO-d6):δ=9.69(s,1H),7.69-7.66(m,2H),7.64-7.62(m,1H),7.59-7.56(m,2H),7.53-7.50(m,2H),7.48-7.46(m,1H),7.38-7.35(m,2H),7.33-7.27(m,3H),7.19-7.16(m,3H),7.13-7.10(m,2H),6.91-6.90(m,2H),6.36-6.34(m,1H),6.32-6.31(m,1H),6.23-6.21(m,1H),5.99(d,J=10.8Hz,1H);13C{1H}NMR(150MHz,DMSO-d6):δ=159.3,158.5,149.8(d,JC-P=10.5Hz),139.4(d,JC-P=61.5Hz),131.8,131.44,131.35,131.2(d,JC-P=7.5Hz),130.8,130.6(d,JC-P=9.0Hz),129.6(d,JC-P=28.5Hz),128.5,128.4,128.3,128.2,127.8,126.5(d,JC-P=57.0Hz),125.6,119.8(d,JC-P=12.0Hz),112.0(d,JC-P=7.5Hz),104.5,97.0,45.6(d,JC-P=58.5Hz);31P{1H}NMR(243MHz,DMSO-d6):δ=28.3;HRMS(ESI):Exact mass calcd for C33H25O3P[M+H]+:501.1614,Found:501.1611.
实施例32化合物32的合成
氮气氛围下,向干燥的25mL Schlenk管中加入3(53.8mg,0.1mmol),苯乙炔(0.3mmol),双三苯基膦二氯化钯(7.0mg,0.01mmol),碘化亚铜(1.9mg,0.01mmol),三乙胺(0.5mL),1.0mL干燥的DMF。加完后移入100℃下继续反应,通过TLC监测反应进程,待反应结束后,经水洗和乙酸乙酯萃取,减压除去溶剂后,用二氯甲烷稀释,加入适量粗硅胶,干法上样柱层析,淋洗剂为石油醚/乙酸乙酯=l/1,得到白色固体32,产率72%。熔点:173-175℃;1H NMR(600MHz,CDCl3):δ=7.71-7.67(m,4H),7.57-7.55(m,2H),7.48-7.46(m,2H),7.45-7.42(m,4H),7.32-7.29(m,3H),7.26-7.23(m,4H),7.22-7.20(m,2H),7.17-7.16(m,4H),7.023-7.022(m,1H),6.95(s,1H),6.13(s,1H),3.89(s,3H);13C{1H}NMR(150MHz,CDCl3):δ=165.6(d,JC-P=16.5Hz),158.4,155.4(d,JC-P=12.0Hz),140.5,132.4(d,JC-P=109.5Hz),132.3,131.8,131.7,131.5,129.0,128.8(d,JC-P=13.5Hz),128.3,128.2,128.0,126.8,125.8,123.4,121.1(d,JC-P=10.5Hz),109.5,107.2(d,JC-P=115.5Hz),94.7,92.6,85.6,56.2,48.9;31P{1H}NMR(243MHz,CDCl3):δ=22.1;HRMS(ESI):Exact masscalcd forC42H31O3P[M+H]+:615.2084,Found:615.2083.
尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (3)
3.根据权利要求2所述的制备方法,其特征在于,加入第二溶剂后的反应温度为80℃。
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---|---|---|---|---|
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CN110256493A (zh) * | 2019-07-09 | 2019-09-20 | 成都大学 | 一种c2-膦酰基吲哚化合物及其制备方法 |
Non-Patent Citations (1)
Title |
---|
Dearomative 1,6-addition of P(O)-H to in situ Formed p-QMs-like Ion Pair from 2-Benzofuryl-ols to C3-Phosphinoyl Hydrobenzofurans;Long Chen,等;Org. Chem. Front.;第8卷(第8期);第1756-1763页 * |
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