CN109134306B - 一种烷基酮酰胺和其肟酰胺类化合物及其制备与应用 - Google Patents
一种烷基酮酰胺和其肟酰胺类化合物及其制备与应用 Download PDFInfo
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- CN109134306B CN109134306B CN201810964067.5A CN201810964067A CN109134306B CN 109134306 B CN109134306 B CN 109134306B CN 201810964067 A CN201810964067 A CN 201810964067A CN 109134306 B CN109134306 B CN 109134306B
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 5
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- 229910052723 transition metal Inorganic materials 0.000 description 1
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Abstract
本发明涉及一种烷基酮酰胺和其肟酰胺类化合物及其制备与应用。本发明提供的一种烷基酮酰胺类化合物及其衍生物可以应用在金属钯催化的C‑H键氟化反应中,可以获得较佳的反应收率、区域选择性,并且一些天然产物也可以应用该方法引入氟原子,进行底物的后期修饰,极大地提高了此类反应的应用价值。
Description
技术领域
本发明涉及一种烷基酮酰胺和其肟酰胺类化合物及其制备与应用,该类化合物可应用于钯催化的C-H键氟化反应合成一系列β-氟代烷基醇,具有优异的反应收率和区域选择性。
背景技术
丙酮酸普遍存在于生物体内,是细胞糖代谢和物质相互转化的关键中间体;同时,丙酮酸还是一种重要的化工原料,在化学、制药以及农化品等工业领域及科学研究中有着广泛应用。但是,作为一类结构简单的有机酸甚少用于辅助过渡金属催化C-H键活化官能化反应。目前此类辅助基团应用较多的为其同系物乙醛酸,所能实现的反应类型也比较局限。与乙醛酸相比,丙酮酸具有更低的毒性,更易于保存的特点,从而在有机反应中具有更广阔的应用前景。另一方面,因为氟原子在功能分子中表现出的优异特性和传统引入氟原子方法上的局限性,利用C(sp3)-H键活化在分子中引入氟原子的策略也早有人使用。然而,目前这些策略只能实现烷基酸的氟化反应,对于有机分子中一类重要的类型烷基醇并不能顺利地引入单氟原子。为了解决这些问题,我们设计了一种新颖的以烷基酮酰胺和其肟酰胺为骨架分子的烷基醇C(sp3)-H键活化策略来直接构建C-F键,从而在烷基醇的位高选择性、高效率地引入一个氟原子。该烷基酰胺骨架分子与钯催化剂结合,能很好地实现目标分子预定位置活化的目的,无论是甲基或者是亚甲基、环型亚甲基都能得到相应的氟化产物。因此这些骨架分子对于钯催化的烷基醇C-H键官能化反应范围的拓展和类型的丰富都具有重要的意义。
发明内容
本发明的目的是提供一种烷基酮酰胺和其肟酰胺类化合物、制备方法以及其在辅助烷基醇β位C(sp3)-H键活化构建β-F烷基醇衍生物中的应用。
本发明提供的制备方法是一种高效的以烷基酮酸化合物为原料合成相应的烷基酮酰胺和其肟酰胺类化合物的方法。
本发明所合成的烷基酮酰胺和其肟酰胺类化合物可以与烷基卤代烷连接,然后在钯催化剂的作用下高效地合成β-F烷基醇衍生物。
本发明所述的烷基酮酰胺类化合物的结构式为:
进一步,所述芳基的R5、R6、R7、R8、R9各自独立为氢、C1~C6的直链或支链脂肪烷基、C1~C6的烷氧基、苄基、苄氧基、C2~C6的烷氧羰基、C2~C6的酰基、三氟甲基、三氟甲氧基、卤素或C6~C10的芳香基;
所述卤素为F、Cl、Br或I。
更进一步,优选所述R5、R6、R7、R8、R9各自独立为氢、甲基、正丁基、叔丁基、甲氧基、苯基、氟、甲氧羰基、乙酰基、三氟甲基、三氟甲氧基、喹啉基;
更优选的,所述R5为氢、氟、甲基、三氟甲基;
R6为氢、氟、三氟甲基;
R7为氢、氟、甲基、三氟甲基;
R8为氢、氟、三氟甲基;
R9为氢、氟、甲基、三氟甲基。
本发明所述的烷基酮酰胺类化合物III是在以烷基酮酸类化合物和伯胺为原料酰胺化制得;其肟酰胺类化合物IV是以式III所示化合物为原料,与盐酸羟胺、碱肟化制得,可以用以下反应式1和2表示:
反应式1:
反应式2:
以上反应式中,DMF表示N,N-二甲基甲酰胺;其中R1,R2同上所述。
以上反应式1中,第一步酰氯化反应结束后建议减压蒸除多余的酰氯化试剂,然后加入溶剂和伯胺。
以上反应式1中,所述的酰氯化试剂可以是草酰氯、二氯亚砜或固体光气;所述的有机溶剂可以是极性或非极性溶剂,如二氯甲烷、二氯亚砜、三氯甲烷、四氯化碳、四氢呋喃、***、甲苯、二甲苯、苯、环己烷、正己烷、二氧六环、乙腈、乙酸乙酯等,推荐二氯甲烷或甲苯。
以上反应式2中,所述的碱可以是有机碱或无机碱,如乙酸钠、乙酸钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠或氢氧化钾;所述的溶剂为甲醇、乙醇、异丙醇或其中任何一种与水的混合溶剂,推荐乙醇与水体积比为3∶1的混合溶剂。
以上反应式1中,所述的烷基酮酸I、酰氯化试剂、DMF、伯胺的摩尔比为(1.2~3.0)∶(1.3~20.0)∶(0.1~0.5)∶1,反应温度为0℃~120℃,反应时间为2h~24h。
以上反应式2中,所述的式III化合物、盐酸羟胺、碱的摩尔比为1∶(1.0~3.0)∶(1.0~6.0),反应温度为60~90℃,反应时间为2h~12h。
以上反应式1的步骤中,所述反应的后处理过程为:用水洗涤三次,无水硫酸钠干燥,过滤,减压浓缩得粗产物。
以上反应式2的步骤中,所述反应的后处理过程为:减压蒸馏除去醇类溶剂,浓缩液加入水,***萃取三次,无水硫酸钠干燥,过滤,减压浓缩得粗产物。
采用本方法所得的粗产物III和IV可以经过重结晶,柱层析等方法加以分离纯化。如用重结晶的方法,推荐溶剂为极性溶剂和非极性溶剂的混合溶剂。推荐溶剂为二氯甲烷-石油醚,二氯甲烷-正己烷,乙酸乙酯-石油醚,乙酸乙酯-正己烷等混合溶剂。用柱层析方法,所用的展开剂为乙酸乙酯-石油醚。
本发明所述的以烷基酮酰胺类化合物为骨架的烷基醇衍生物V的结构为:
本发明所述的烷基醇衍生物V的制备方法包括下述步骤:将烷基肟酰胺IV与烷基卤代物进行醚化反应,即可制得化合物V,可以用反应式3表示:
反应式3:
以上反应式3中,TBAB表示四丁基溴化铵;R1,R2,R3,R4同上;X为氯、溴或碘。
本发明方法中,所述溶剂为二氯甲烷、三氯甲烷、四氯化碳、四氢呋喃、***、甲苯、二甲苯、苯、环己烷、正己烷、二氧六环、乙腈、乙酸乙酯、N,N-二甲基甲酰胺、水或其中两种的混合溶剂,推荐四氢呋喃和水的混合溶剂。
以上反应式3中,化合物IV、烷基卤代物、氢氧化钠、四丁基溴化铵的摩尔比为1∶(1.0~3.0)∶(1.0~3.0)∶(0.05~0.2);反应温度为60~80℃,反应时间为1h~5h。
以上反应式3的步骤中,所述反应的后处理过程为:减压蒸除有机溶剂,浓缩液加入水,***萃取三次,无水硫酸钠干燥,过滤,减压浓缩得粗产物。
采用本方法所得的粗产物V优选使用柱层析的方法提纯,所用的洗脱剂为极性和非极性的混合溶剂,如乙酸乙酯-石油醚、乙酸乙酯-正己烷等。
本发明还提供了在钯催化剂的作用下所述化合物V的β位C(sp3)-H键活化直接构建β-F烷基醇衍生物的反应中的应用。
较佳的,所述方法的应用包括如下步骤:在有机溶剂中,化合物V、钯化合物、N-氟代双苯磺酰胺、碱、添加剂相继加入反应可得β-F烷基醇衍生物VI,可用反应式4表示:
反应式4:
以上反应式4中,Pd源表示钯化合物,NFSI表示N-氟代双苯磺酰胺,R1,R2,R3,R4同上。
其中,所述钯化合物为醋酸钯、三氟乙酸钯、二(乙酰丙酮)钯或四(三苯基膦)钯,推荐醋酸钯。
其中,所述的碱为碳酸银或乙酸银。
其中,所述添加剂为色氨酸、酪氨酸、半胱氨酸、谷氨酸、缬氨酸、苯甘氨酸、亮氨酸等,推荐亮氨酸。
其中,所述溶剂为二氯甲烷、氯仿、1,2-二氯乙烷、甲苯、氯苯或***,较佳的为1,2-二氯乙烷或氯苯。
其中,所述的化合物V,钯化合物,NFSI,碱,添加剂的摩尔比为1∶(0.05~0.2)∶(1.0~3.0)∶(0.0~3.0)∶(0.0~0.2);反应时间为12~48h。
所述的烷基醇衍生物β位C(sp3)-H氟化反应的温度为50~140℃,较佳的为65~120℃。
本发明所提供的一种烷基酮酰胺类化合物及其衍生物可以应用在金属钯催化的C-H键氟化反应中,可以获得较佳的反应收率、区域选择性。并且一些天然产物也可以应用该方法引入氟原子,进行底物的后期修饰,极大地提高了此类反应的应用价值。
具体实施方式
通过下述实施例将有助于理解本发明,但不限制本发明的内容。
实施例1:
III1的合成:在1L圆底烧瓶中加入丙酮酸11.0g(125mmol),二氯甲烷300mL,冷却至0℃,滴加草酰氯16.5g(130mmol),N,N-二甲基甲酰胺10滴。反应在室温下搅拌4h,然后减压蒸馏除去溶剂和多余的草酰氯。剩余物溶解在400mL甲苯中,然后加入五氟苯胺9.15g(50mmol),所得混合液回流反应30分钟,TLC检测反应终点。反应冷却至室温,减压蒸馏除去甲苯,剩余物溶解于100mL二氯甲烷中,用100mL水洗涤三次,硫酸钠干燥,过滤,浓缩得黄色粗产物III1 11.0g(87%收率)。该粗产物可直接用于下步反应。
IV1的合成:在500mL圆底烧瓶中加入III1 10.1g(40mmol),盐酸羟胺6.1g(88mmol),乙酸钠14.4g(176mmol),乙醇120mL,水40mL。反应液加热至85℃回流3.5h。反应结束后,减压蒸馏除去乙醇,剩余水溶液用二氯甲烷(50mL)萃取三次。所得有机相用硫酸钠干燥,过滤,浓缩,得淡黄色固体IV1 10.2g(95%收率)。
实施例2:
III2的合成:在1L圆底烧瓶中加入丙酮酸5.3g(60mmol),二氯甲烷300mL,冷却至0℃,滴加草酰氯9.1g(72mmol),N,N-二甲基甲酰胺10滴。反应在室温下搅拌4h,然后减压蒸馏除去溶剂和多余的草酰氯。剩余物溶解在400mL甲苯中,然后加入环己胺5.0g(50mmol),所得混合液回流反应30分钟,TLC检测反应终点。反应冷却至室温,减压蒸馏除去甲苯,剩余物溶解于100mL二氯甲烷中,用100mL水洗涤三次,硫酸钠干燥,过滤,浓缩得黄色粗产物III27.4g(87%收率)。该粗产物可直接用于下步反应。
IV2的合成:在500mL圆底烧瓶中加入III26.8g(40mmol),盐酸羟胺6.1g(88mmol),乙酸钠14.4g(176mmol),乙醇120mL,水40mL。反应液加热至85℃回流3.5h。反应结束后,减压蒸馏除去乙醇,剩余水溶液用二氯甲烷(50mL)萃取三次。所得有机相用硫酸钠干燥,过滤,浓缩,得淡黄色固体IV1 6.85g(93%收率)。
实施例3:
III3的合成:在1L圆底烧瓶中加入丙酮酸5.3g(60mmol),二氯甲烷300mL,冷却至0℃,滴加二氯亚砜10.7g(90mmol),N,N-二甲基甲酰胺10滴。反应在室温下搅拌4h,然后减压蒸馏除去溶剂和多余的二氯亚砜。剩余物溶解在400mL甲苯中,然后加入苯胺4.7g(50mmol),所得混合液回流反应30分钟,TLC检测反应终点。反应冷却至室温,减压蒸馏除去甲苯,剩余物溶解于100mL二氯甲烷中,用100mL水洗涤三次,硫酸钠干燥,过滤,浓缩得黄色粗产物III37.3g(90%收率)。该粗产物可直接用于下步反应。
IV3的合成:在500mL圆底烧瓶中加入III36.5g(40mmol),盐酸羟胺6.1g(88mmol),乙酸钾17.3g(176mmol),乙醇120mL,水40mL。反应液加热至85℃回流3.5h。反应结束后,减压蒸馏除去乙醇,剩余水溶液用二氯甲烷(50mL)萃取三次。所得有机相用硫酸钠干燥,过滤,浓缩,得淡黄色固体IV36.8g(96%收率)。
实施例4:
III4的合成:在1L圆底烧瓶中加入丙酮酸11.0g(125mmol),甲苯300mL,冷却至0℃,滴加草酰氯16.5g(130mmol),N,N-二甲基甲酰胺10滴。反应在室温下搅拌4h,然后减压蒸馏除去溶剂和多余的草酰氯。剩余物溶解在400mL甲苯中,然后加入均三甲苯胺6.8g(50mmol),所得混合液回流反应30分钟,TLC检测反应终点。反应冷却至室温,减压蒸馏除去甲苯,剩余物溶解于100mL二氯甲烷中,用100mL水洗涤三次,硫酸钠干燥,过滤,浓缩得黄色粗产物III48.7g(85%收率)。该粗产物可直接用于下步反应。
IV4的合成:在500mL圆底烧瓶中加入III48.2g(40mmol),盐酸羟胺6.1g(88mmol),碳酸钾24.3g(176mmol),甲醇120mL,水40mL。反应液加热至85℃回流3.5h。反应结束后,减压蒸馏除去甲醇,剩余水溶液用二氯甲烷(50mL)萃取三次。所得有机相用硫酸钠干燥,过滤,浓缩,得淡黄色固体IV1 8.1g(92%收率)。
实施例5:
III5的合成:在1L圆底烧瓶中加入丙酮酸11.0g(125mmol),二氯甲烷300mL,冷却至0℃,滴加草酰氯16.5g(130mmol),N,N-二甲基甲酰胺10滴。反应在室温下搅拌4h,然后减压蒸馏除去溶剂和多余的草酰氯。剩余物溶解在400mL甲苯中,然后加入3,5-二三氟甲基苯胺11.5g(50mmol),所得混合液常温反应30分钟,TLC检测反应终点。减压蒸馏除去甲苯,剩余物溶解于100mL二氯甲烷中,用100mL水洗涤三次,硫酸钠干燥,过滤,浓缩得淡黄色固体III514.2g(95%收率)。该粗产物可直接用于下步反应。
IV5的合成:在500mL圆底烧瓶中加入III512.0g(40mmol),盐酸羟胺6.1g(88mmol),乙酸钠14.4g(176mmol),四氢呋喃120mL,水40mL。反应液加热至85℃回流3.5h。反应结束后,减压蒸馏除去四氢呋喃,剩余水溶液用二氯甲烷(50mL)萃取三次。所得有机相用硫酸钠干燥,过滤,浓缩,得淡黄色固体IV512.1g(96%收率)。
实施例6:
III6的合成:在1L圆底烧瓶中加入丙酮酸11.0g(125mmol),二氯甲烷300mL,冷却至0℃,滴加草酰氯16.5g(130mmol),N,N-二甲基甲酰胺10滴。反应在室温下搅拌4h,然后减压蒸馏除去溶剂和多余的草酰氯。剩余物溶解在400mL甲苯中,然后加入2,6-二氟苯胺6.5g(50mmol),所得混合液回流反应30分钟,TLC检测反应终点。反应冷却至室温,减压蒸馏除去甲苯,剩余物溶解于100mL二氯甲烷中,用100mL水洗涤三次,硫酸钠干燥,过滤,浓缩得黄色粗产物III68.9g(89%收率)。该粗产物可直接用于下步反应。
IV6的合成:在500mL圆底烧瓶中加入III68.0g(40mmol),盐酸羟胺6.1g(88mmol),乙酸钠14.4g(176mmol),乙醇120mL,水40mL。反应液加热至85℃回流3.5h。反应结束后,减压蒸馏除去乙醇,剩余水溶液用二氯甲烷(50mL)萃取三次。所得有机相用硫酸钠干燥,过滤,浓缩,得淡黄色固体IV67.9g(92%收率)。
实施例7:
III7的合成:在1L圆底烧瓶中加入丙酮酸5.3g(60mmol),二氯甲烷300mL,冷却至0℃,滴加草酰氯9.1g(72mmol),N,N-二甲基甲酰胺10滴。反应在室温下搅拌4h,然后减压蒸馏除去溶剂和多余的草酰氯。剩余物溶解在400mL甲苯中,然后加入对氯苯胺6.4g(50mmol),所得混合液回流反应30分钟,TLC检测反应终点。反应冷却至室温,减压蒸馏除去甲苯,剩余物溶解于100mL二氯甲烷中,用100mL水洗涤三次,硫酸钠干燥,过滤,浓缩得黄色粗产物III78.2g(83%收率)。该粗产物可直接用于下步反应。
IV7的合成:在500mL圆底烧瓶中加入III77.9g(40mmol),盐酸羟胺6.1g(88mmol),乙酸钠14.4g(176mmol),乙醇120mL,水40mL。反应液加热至85℃回流3.5h。反应结束后,减压蒸馏除去乙醇,剩余水溶液用二氯甲烷(50mL)萃取三次。所得有机相用硫酸钠干燥,过滤,浓缩,得淡黄色固体IV78.0g(94%收率)。
实施例8:
III8的合成:在1L圆底烧瓶中加入丙酮酸5.3g(60mmol),二氯甲烷300mL,冷却至0℃,滴加草酰氯9.1g(72mmol),N,N-二甲基甲酰胺10滴。反应在室温下搅拌4h,然后减压蒸馏除去溶剂和多余的草酰氯。剩余物溶解在400mL二氯甲烷中,然后加入对甲氧基苯胺6.2g(50mmol),所得常温搅拌30分钟,TLC检测反应终点。反应冷却至室温,减压蒸馏除去二氯甲烷,剩余物溶解于100mL二氯甲烷中,用100mL水洗涤三次,硫酸钠干燥,过滤,浓缩得黄色粗产物III88.4g(87%收率)。该粗产物可直接用于下步反应。
IV8的合成:在500mL圆底烧瓶中加入III87.7g(40mmol),盐酸羟胺6.1g(88mmol),乙酸钠14.4g(176mmol),乙醇120mL,水40mL。反应液加热至85℃回流3.5h。反应结束后,减压蒸馏除去乙醇,剩余水溶液用二氯甲烷(50mL)萃取三次。所得有机相用硫酸钠干燥,过滤,浓缩,得淡黄色固体IV88.0g(96%收率)。
实施例9:
III9的合成:在1L圆底烧瓶中加入丙酮酸5.3g(60mmol),二氯甲烷300mL,冷却至0℃,滴加草酰氯9.1g(72mmol),N,N-二甲基甲酰胺10滴。反应在室温下搅拌4h,然后减压蒸馏除去溶剂和多余的草酰氯。剩余物溶解在400mL甲苯中,然后加入对三氟甲氧基苯胺8.9g(50mmol),所得混合液回流反应30分钟,TLC检测反应终点。反应冷却至室温,减压蒸馏除去甲苯,剩余物溶解于100mL二氯甲烷中,用100mL水洗涤三次,硫酸钠干燥,过滤,浓缩得黄色粗产物III910.5g(85%收率)。该粗产物可直接用于下步反应。
IV9的合成:在500mL圆底烧瓶中加入III99.9g(40mmol),盐酸羟胺6.1g(88mmol),乙酸钠14.4g(176mmol),乙醇120mL,水40mL。反应液加热至85℃回流3.5h。反应结束后,减压蒸馏除去乙醇,剩余水溶液用二氯甲烷(50mL)萃取三次。所得有机相用硫酸钠干燥,过滤,浓缩,得淡黄色固体IV910.0g(95%收率)。
实施例10:
III10的合成:在1L圆底烧瓶中加入丙酮酸5.3g(60mmol),二氯甲烷300mL,冷却至0℃,滴加草酰氯9.1g(72mmol),N,N-二甲基甲酰胺10滴。反应在室温下搅拌4h,然后减压蒸馏除去溶剂和多余的草酰氯。剩余物溶解在400mL甲苯中,然后加入对叔丁基苯胺7.5g(50mmol),所得混合液回流反应30分钟,TLC检测反应终点。反应冷却至室温,减压蒸馏除去甲苯,剩余物溶解于100mL二氯甲烷中,用100mL水洗涤三次,硫酸钠干燥,过滤,浓缩得黄色粗产物III109.9g(90%收率)。该粗产物可直接用于下步反应。
IV10的合成:在500mL圆底烧瓶中加入III108.8g(40mmol),盐酸羟胺6.1g(88mmol),乙酸钠14.4g(176mmol),乙醇120mL,水40mL。反应液加热至85℃回流3.5h。反应结束后,减压蒸馏除去乙醇,剩余水溶液用二氯甲烷(50mL)萃取三次。所得有机相用硫酸钠干燥,过滤,浓缩,得淡黄色固体IV109.1g(97%收率)。
实施例11:
III11的合成:在1L圆底烧瓶中加入丙酮酸5.3g(60mmol),二氯甲烷300mL,冷却至0℃,滴加草酰氯9.1g(72mmol),N,N-二甲基甲酰胺10滴。反应在室温下搅拌4h,然后减压蒸馏除去溶剂和多余的草酰氯。剩余物溶解在400mL甲苯中,然后加入8-氨基喹啉7.2g(50mmol),所得混合液回流反应30分钟,TLC检测反应终点。反应冷却至室温,减压蒸馏除去甲苯,剩余物溶解于100mL二氯甲烷中,用100mL水洗涤三次,硫酸钠干燥,过滤,浓缩得黄色粗产物III11 9.2g(86%收率)。该粗产物可直接用于下步反应。
IV11的合成:在500mL圆底烧瓶中加入III11 8.6g(40mmol),盐酸羟胺6.1g(88mmol),乙酸钠14.4g(176mmol),乙醇120mL,水40mL。反应液加热至85℃回流3.5h。反应结束后,减压蒸馏除去乙醇,剩余水溶液用二氯甲烷(50mL)萃取三次。所得有机相用硫酸钠干燥,过滤,浓缩,得淡黄色固体IV11 8.3g(91%收率)。
实施例12:
III12的合成:在1L圆底烧瓶中加入2-丁酮酸12.8g(125mmol),二氯甲烷300mL,冷却至0℃,滴加草酰氯16.5g(130mmol),N,N-二甲基甲酰胺10滴。反应在室温下搅拌4h,然后减压蒸馏除去溶剂和多余的草酰氯。剩余物溶解在400mL甲苯中,然后加入五氟苯胺9.15g(50mmol),所得混合液回流反应30分钟,TLC检测反应终点。反应冷却至室温,减压蒸馏除去甲苯,剩余物溶解于100mL二氯甲烷中,用100mL水洗涤三次,硫酸钠干燥,过滤,浓缩得黄色粗产物III1211.4g(85%收率)。该粗产物可直接用于下步反应。
IV12的合成:在500mL圆底烧瓶中加入III1210.7g(40mmol),盐酸羟胺6.1g(88mmol),乙酸钠14.4g(176mmol),乙醇120mL,水40mL。反应液加热至85℃回流3.5h。反应结束后,减压蒸馏除去乙醇,剩余水溶液用二氯甲烷(50mL)萃取三次。所得有机相用硫酸钠干燥,过滤,浓缩,得淡黄色固体IV1210.4g(92%收率)。
应用实施例13:
一般反应操作:V1的合成:在50mL圆底烧瓶中加入IV1 0.54g(2.0mmol),四丁基溴化铵77.3mg(0.24mmol),氢氧化钠0.12g(3.0mmol),四氢呋喃14mL和水7mL,所得混合液加热至65℃,然后滴加2-碘代正戊烷的四氢呋喃溶液3mL(1mol/L),并在此温度下反应3.5h。反应结束后,减压蒸馏除去四氢呋喃,剩余水相用二氯甲烷(15mL)萃取三次。混合有机层,无水硫酸钠干燥,过滤,浓缩,粗产物通过柱层析分离(石油醚/乙酸乙酯:50/1)。
一般反应操作:Vl1的合成::在10mL封管中加入烷基醇衍生物V1(0.3mmol),醋酸钯6.8mg(0.03mmol),NFSI 189.0mg(0.6mmol),氯苯3.0mL,指定温度下反应24h。反应结束后,冷却至室温,用二氯甲烷稀释,减压蒸馏除去溶剂,柱层析提纯(石油醚/乙酸乙酯:50/1)。
75℃;无色液体;85%收率;1H NMR(500MHz,CDCl3):δ=8.09(s,1H),4.67-4.59(m,1H),4.53-4.45(m,2H),2.14(s,3H),1.82-1.74(m,1H),1.71-1.64(m,1H),1.55-1.44(m,2H),1.00(t,J=7.4Hz,3H)ppm;13C NMR(125MHz,CDCl3):δ=161.1,150.2,144.2-144.0(m),142.2-142.0(m),141.2-140.9(m),139.2-138.7(m),137.0-136.7(m),111.7-111.4(m),83.7(d,J=173.7Hz),83.5(d,J=18.7Hz),31.50(d,J=5.5Hz),18.5,13.9,9.9ppm;19F NMR(376MHz,CDCl3):δ-144.5-(-144.6)(m,2F),-156.6(t,J=21.5Hz,1F),-162.2-(-162.4)(m,2F),-230.0(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+379.0852Found:379.0852.
110℃;无色液体;66%收率;1H NMR(500MHz,CDCl3):δ=8.08(s,1H),4.78-4.77(m,1H),4.69-4.67(m,1H),4.57-4.55(m,1H),4.51-4.49(m,1H),2.16(s,3H)ppm;13C NMR(125MHz,CDCl3):δ=160.9,150.8,144.2-143.9(m),142.2-142.0(m),141.3-141.2(m),139.0-138.7(m),136.8-136.6(m),111.5-111.3(m),81.6(d,J=171.2Hz),74.6(d,J=19.8Hz),10.0ppm;19F NMR(376MHz,CDCl3):δ-144.4-(-144.5)(m,2F),-156.4(t,J=21.5Hz,1F),-162.1-(-162.2)(m,2F),-225.2(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+337.0382Found:337.0382.
75℃;白色固体;50%收率;1H NMR(500MHz,CDCl3):δ=8.04(s,1H),4.44(d,J=47.6Hz,2H),2.13(s,3H),1.42(d,J=2.2Hz,6H)ppm;13C NMR(125MHz,CDCl3):δ=161.3,150.1,144.1-144.0(m),142.2-142.0(m),141.2-141.0(m),139.1-138.8(m),137.0-136.8(m),111.8-111.4(m),86.71(d,J=178.0Hz),81.63(d,J=17.9Hz),22.03(d,J=4.6Hz,2C),9.9ppm;19F NMR(376MHz,CDCl3):δ-144.6-(-144.7)(m,2F),-156.7(t,J=21.6Hz,1F),-162.2-(-162.3)(m,2F),-226.9(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+365.0695Found:365.0695.
75℃;白色固体;86%收率;1H NMR(500MHz,CDCl3):δ=8.10(s,1H),4.74-4.57(m,2H),4.29-4.21(m,1H),2.15(s,3H),1.90-1.71(m,6H),1.32-1.09(m,5H)ppm;13C NMR(125MHz,CDCl3):δ=161.1,150.0,144.2-144.0(m),142.1-142.0(m),141.1-140.9(m),139.1-138.7(m),137.0-136.7(m),111.7-111.4(m),88.2(d,J=18.1Hz),82.5(d,J=172.9Hz),38.2(d,J=5.2Hz),28.9,28.7,26.2,26.0,25.9,9.9ppm;19F NMR(376MHz,CDCl3):δ-144.5-(-144.6)(m,2F),-156.7(t,J=21.6Hz,1F),-162.3-(-162.4)(m,2F),-231.4(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+ 419.1165Found:419.1165.
75℃;无色液体;84%收率;1H NMR(500MHz,CDCl3):δ=7.89(s,1H),7.36-7.33(m,2H),7.28-7.26(m,3H),4.74-4.49(m,3H),3.14-3.05(m,2H),2.14(s,3H)ppm;13C NMR(125MHz,CDCl3):δ=160.9,150.6,144.2-144.0(m),142.2-142.0(m),141.2-141.1(m),139.1-138.7(m),136.9-136.6(m),136.6,129.4(2C),128.6(2C),126.9,111.5-111.3(m),84.3(d,J=18.7Hz),82.7(d,J=174.1Hz),36.1(d,J=5.8Hz),10.1ppm;19F NMR(376MHz,CDCl3):δ-144.4-(-144.5)(m,2F),-156.4(t,J=21.5Hz,1F),-162.2-(-162.3)(m,2F),-231.4(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+427.0852Found:427.0852.
90℃;白色固体;55%收率;1H NMR(500MHz,CDCl3):δ=7.91(s,1H),7.29-7.26(m,2H),6.93-6.90(m,3H),4.89-4.59(m,3H),4.16-4.14(m,2H),2.27-2.23(m,2H),2.15(s,3H)ppm;13C NMR(125MHz,CDCl3):δ=160.9,158.5,150.7,144.2-144.0(m),142.2-142.0(m),141.2-141.0(m),139.1-138.8(m),136.9-136.7(m),129.5(2C),121.0,114.4(2C),111.6-111.3(m),83.7(d,J=174.0Hz),80.7(d,J=19.0Hz),63.3,29.7(d,J=6.1Hz),10.0ppm;19F NMR(376MHz,CDCl3):δ-144.4-(-144.5)(m,2F),-156.5(t,J=21.6Hz,1F),-162.3-(-162.4)(m,2F),-230.1(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+457.0957Found:457.0957.
75℃;白色固体;57%收率;1H NMR(500MHz,CDCl3):δ=8.90(d,J=8.7Hz,1H),8.22(dd,J=7.3,1.2Hz,1H),8.14(s,1H),8.04(d,J=8.2Hz,1H),7.88(d,J=8.6Hz,1H),7.61-7.49(m,3H),4.82-4.67(m,3H),4.66-4.56(m,2H),2.37-2.26(m,2H),2.15(s,3H)ppm;13C NMR(125MHz,CDCl3):δ=167.3,160.9,151.1,144.1-143.9(m),142.1-141.9(m),141.1-141.0(m),138.8-138.5(m),136.8-136.5(m),133.8,133.7,131.3,130.2,128.6,127.9,126.5,126.3,125.5,124.4,111.5-111.2(m),83.5(d,J=174.6Hz),80.6(d,J=19.2Hz),60.9,29.4(d,J=5.8Hz),10.1ppm;19F NMR(376MHz,CDCl3):δ-144.3-(-144.4)(m,2F),-156.6(t,J=21.6Hz,1F),-162.3-(-162.4)(m,2F),-230.0(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+535.1063Found:535.1062.
75℃;白色固体;72%收率;1H NMR(500MHz,CDCl3):δ=8.18(s,1H),4.98(d,J=10.0Hz,1H),4.11(ddd,J1=46.8Hz,J2=11.0Hz,J3=2.7Hz,1H),2.13(s,3H),2.06-1.97(m,1H),1.87-1.82(m,1H),1.73-1.61(m,2H),1.41-1.27(m,2H),1.19-1.13(m,1H),1.06(d,J=6.4Hz,3H),0.99(d,J=6.7Hz,3H),0.95(d,J=6.7Hz,3H)ppm;13C NMR(125MHz,CDCl3):δ=161.3,149.0,144.1-143.9(m),142.1-141.9(m),141.0-140.9(m),139.1-138.6(m),137.0-136.7(m),111.8-111.6(m),98.2(d,J=184.4Hz),83.2(d,J=15.8Hz),47.3(d,J=4.8Hz),32.1(d,J=17.9Hz),31.9(d,J=9.1Hz),28.7,24.1,21.0,20.7,17.6(d,J=2.3Hz),9.8ppm;19F NMR(376MHz,CDCl3):δ-144.5-(-144.6)(m,2F),-157.1(t,J=21.5Hz,1F),-162.5-(-162.6)(m,2F),-187.0(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+447.1478Found:447.1478.
应用实施例14:
一般反应操作:V1的合成:在50mL圆底烧瓶中加入IV1 0.54g(2.0mmol),四丁基溴化铵77.3mg(0.24mmol),氢氧化钠0.12g(3.0mmol),四氢呋喃14mL和水7mL,所得混合液加热至65℃,然后滴加2-碘代正戊烷的四氢呋喃溶液3mL(1mol/L),并在此温度下反应3.5h。反应结束后,减压蒸馏除去四氢呋喃,剩余水相用二氯甲烷(15mL)萃取三次。混合有机层,无水硫酸钠干燥,过滤,浓缩,粗产物通过柱层析分离(石油醚/乙酸乙酯:50/1)。
一般反应操作:VI1的合成:在10mL封管中加入烷基醇衍生物V1(0.3mmol),醋酸钯6.8mg(0.03mmol),NFSI 189.0mg(0.6mmol),碳酸银165.4mg(0.6mmol),L-亮氨酸3.9mg(0.03mmol),氯苯3.0mL,120℃反应24h。反应结束后,冷却至室温,用二氯甲烷稀释,过滤,减压蒸馏除去溶剂,柱层析提纯(石油醚/乙酸乙酯:50/1)。
120℃;无色液体;54%收率;1H NMR(500MHz,CDCl3):δ=8.09(s,1H),4.80-4.65(m,1H),4.43-4.33(m,2H),2.15(s,3H),1.81-1.66(m,2H),1.07(t,J=7.5Hz,3H)ppm;13C NMR(125MHz,CDCl3):δ=160.9,150.5,144.2-144.0(m),142.2-142.1(m),141.1-141.0(m),139.0-138.8(m),137.0-136.8(m),111.6-111.4(m),92.8(d,J=173.0Hz),77.2(d,J=9.7Hz),24.6(d,J=21.3Hz),9.9,9.1(d,J=5.8Hz)ppm;19F NMR(376MHz,CDCl3):δ-144.4-(-144.5)(m,2F),-156.5(t,J=21.4Hz,1F),-162.2-(-162.4)(m,2F),-188.7(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+365.0695Found:365.0695.
120℃;无色液体;57%收率;1H NMR(500MHz,CDCl3):δ=8.04(s,1H),7.35(t,J=7.3Hz,2H),7.30-7.26(m,3H),5.09-4.95(m,1H),4.47-4.35(m,2H),3.14-2.98(m,2H),2.16(s,3H)ppm;13C NMR(125MHz,CDCl3):δ=160.9,150.7,144.2-144.0(m),142.2-142.0(m),141.3-141.0(m),139.0-138.8(m),136.9-136.7(m),135.8(d,J=5.7Hz),129.3(2C),128.7(2C),127.0,111.6-111.2(m),91.8(d,J=176.3Hz),76.4(d,J=22.1Hz),37.9(d,J=21.4Hz),10.0ppm;19F NMR(376MHz,CDCl3):δ-144.4-(-144.5)(m,2F),-156.5(t,J=21.4Hz,1F),-162.2-(-162.3)(m,2F),-185.1(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+427.0852Found:427.0852.
120℃;淡黄色液体;71%收率;1H NMR(500MHz,CDCl3):δ=7.98(s,1H),7.45-7.38(m,5H),5.78(ddd,J1=48.2Hz,J2=7.6Hz,J3=2.9Hz,1H),4.67-4.47(m,2H),2.16(s,3H)ppm;13C NMR(125MHz,CDCl3):δ=160.9,150.8,144.2-144.0(m),142.2-142.0(m),141.3-141.1(m),139.0-138.7(m),137.0-136.7(m),136.0(d,J=19.9Hz),129.0(d,J=1.5Hz),128.7(2C),125.8(d,J=6.9Hz,2C),111.6-111.3(m),92.0(d,J=176.6Hz),78.3(d,J=24.8Hz),10.0ppm;19F NMR(376MHz,CDCl3):δ-144.4-(-144.5)(m,2F),-156.5(t,J=21.4Hz,1F),-162.2-(-162.4)(m,2F),-184.9(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+413.0695Found:413.0696.
120℃;淡黄色液体;41%收率;1H NMR(500MHz,CDCl3):δ=7.97(s,1H),7.67(d,J=5.5Hz,2H),7.62-7.55(m,2H),5.84(ddd,J1=47.6Hz,J2=7.1Hz,J3=3.1Hz,1H),4.75-4.45(m,2H),2.15(s,3H)ppm;13C NMR(125MHz,CDCl3):δ=160.7,151.1,144.2-144.0(m),142.2-142.0(m),141.3-141.1(m),139.2-138.7(m),137.1(d,J=20.6Hz),136.9-136.7(m),131.2(q,J=32.7Hz),129.3,129.0(d,J=7.0Hz),125.86-125.70(m),123.8(q,J=270.7Hz),122.7(dd,J1=7.6Hz,J2=3.9Hz),111.8-111.5(m),91.2(d,J=178.4Hz),77.9(d,J=24.4Hz),10.1ppm;19F NMR(376MHz,CDCl3):δ-144.5-(-144.6)(m,2F),-156.6(t,J=21.5Hz,1F),-162.2-(-162.4)(m,2F),-230.0(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+481.0569Found:481.0569.
120℃;无色液体;72%收率;1H NMR(500MHz,CDCl3):δ=7.79(s,1H),7.43-7.39(m,5H),5.99(dd,J1=45.2Hz,J2=4.4Hz,1H),5.11(dd,J1=24.1Hz,J2=4.4Hz,1H),3.77(s,3H),2.17(s,3H)ppm;13C NMR(125MHz,CDCl3):δ=167.9(d,J=6.1Hz),160.4,152.2,144.2-144.0(m),142.1-142.0(m),141.3-141.1(m),139.3-138.8(m),137.1-136.7(m),134.6(d,J=20.7Hz),129.3(d,J=1.0Hz),128.6(2C),126.1(d,J=7.0Hz,2C),111.5-111.1(m),92.2(d,J=182.6Hz),85.5(d,J=23.0Hz),52.7,10.3ppm;19F NMR(376MHz,CDCl3):δ-144.3-(-144.4)(m,2F),-156.3(t,J=21.3Hz,1F),-162.1-(-162.3)(m,2F),-189.6(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+471.0750Found:471.0749.
应用实施例15:
V5-1的合成:在50mL圆底烧瓶中加入IV-50.63g(2.0mmol),四丁基溴化铵77.3mg(0.24mmol),氢氧化钠0.12g(3.0mmol),四氢呋喃14mL和水7mL,所得混合液加热至65℃,然后滴加2-碘代正戊烷的四氢呋喃溶液3mL(1mol/L),并在此温度下反应3.5h。反应结束后,减压蒸馏除去四氢呋喃,剩余水相用二氯甲烷(15mL)萃取三次。混合有机层,无水硫酸钠干燥,过滤,浓缩,粗产物通过柱层析分离(石油醚/乙酸乙酯:50/1)。
VI5-1的合成:在10mL封管中加入烷基醇衍生物V5-1(0.3mmol),醋酸钯6.8mg(0.03mmol),NFSI 189.0mg(0.6mmol),氯苯3.0mL,75℃反应24h。反应结束后,冷却至室温,用二氯甲烷稀释,减压蒸馏除去溶剂,柱层析提纯(石油醚/乙酸乙酯:50/1),产物收率由气相色谱测定(71%收率)。
应用实施例16:
V6-1的合成:在50mL圆底烧瓶中加入IV60.43g(2.0mmol),四丁基溴化铵77.3mg(0.24mmol),氢氧化钠0.12g(3.0mmol),四氢呋喃14mL和水7mL,所得混合液加热至65℃,然后滴加2-碘代正戊烷的四氢呋喃溶液3mL(1mol/L),并在此温度下反应3.5h。反应结束后,减压蒸馏除去四氢呋喃,剩余水相用二氯甲烷(15mL)萃取三次。混合有机层,无水硫酸钠干燥,过滤,浓缩,粗产物通过柱层析分离(石油醚/乙酸乙酯:50/1)。
VI6-1的合成:在10mL封管中加入烷基醇衍生物V6-1(0.3mmol),醋酸钯6.8mg(0.03mmol),NFSI 189.0mg(0.6mmol),氯苯3.0mL,75℃反应24h。反应结束后,冷却至室温,用二氯甲烷稀释,减压蒸馏除去溶剂,柱层析提纯(石油醚/乙酸乙酯:50/1),产物收率由气相色谱测定(90%收率)。
应用实施例17:
VI1-7中烷基肟酰胺辅助基团的脱除:在25mL Schlenk管中加入VI1-741mg(0.08mmol),六羰基钼26.4mg(0.1mmol),乙腈2mL,水4滴。该Schlenk管用聚四氟乙烯螺纹盖封管,使用真空线排空气和充氮气三次,然后回流反应12h。反应结束后,冷却至室温,用二氯甲烷稀释,减压蒸馏除去溶剂,柱层析提纯(石油醚/乙酸乙酯:3/1),得β-氟代烷基醇VII1-718mg(85%收率)。
无色液体;1H NMR(500MHz,CDCl3):δ=8.92(d,J=8.7Hz,1H),8.19(d,J=6.9Hz,1H),8.05(d,J=8.2Hz,1H),7.91(d,J=8.1Hz,1H),7.64(t,J=7.7Hz,1H),7.54(dt,J1=22.6Hz,J2=7.7Hz,2H),4.72-4.67(m,1H),4.60-4.54(m,1.5H),4.47-4.44(m,1H),4.38-4.35(m,0.5H),4.18-4.10(m,1H),2.64(brs,1H)2.09-2.02(m,1H),2.00-1.93(m,1H)ppm;13C NMR(125MHz,CDCl3):δ=167.7,133.9,133.6,131.3,130.2,128.6,127.9,126.8,126.3,125.7,124.5,86.7(d,J=169.7Hz),67.6(d,J=19.6Hz),61.4,31.5(d,J=6.8Hz)ppm;19F NMR(376MHz,CDCl3):δ-228.3(s,1F)ppm;HRMS(ESI-TOF):calcd.[M+Na]+285.0897;found:285.0902.
Claims (6)
1.一种基于烷基酮酰胺类化合物为骨架的烷基醇衍生物的应用,其特征在于,所述的应用包括下述步骤:在有机溶剂中,50℃-140℃下,将烷基醇衍生物V、钯化合物、N-氟代双苯磺酰胺、碱、添加剂相继加入进行C(sp3)-H键氟化反应;
反应式为:
所述的烷基醇衍生物V、钯化合物、N-氟代双苯磺酰胺、碱、添加剂的摩尔比为1:(0.05~0.2):(1.0~3.0):(0.0~3.0):(0.0~0.2);
所述的烷基醇衍生物V在C(sp3)-H键氟化反应中的反应时间为12~48h;
所述的钯化合物为醋酸钯、三氟乙酸钯、二(乙酰丙酮)钯或四(三苯基膦)钯;
所述的碱为碳酸银或乙酸银;
所述的添加剂为色氨酸、酪氨酸、半胱氨酸、谷氨酸、缬氨酸、苯甘氨酸、或亮氨酸;
所述的溶剂为二氯甲烷、氯仿、1,2-二氯乙烷、甲苯、氯苯或***;
所述的烷基醇衍生物V为具有如下结构的化合物:
其中,R1选自H或C1~C16烷基;
R2选自C1~C16烷基、C3~C16环烷基或芳基;
R3选自H、C2~C16烷基、C3~C16环烷基、烷氧基、苯氧基、C2~C16酯基、苄基或取代苄基或烷氧甲酰基;
R4选自H、C1~C16烷基、苄基或取代苄基。
3.根据权利要求2所述的烷基醇衍生物的应用,其特征在于,R5、R6、R7、R8、R9各自独立为氢、甲基、正丁基、叔丁基、甲氧基、苯基、氟、甲氧羰基、乙酰基、三氟甲基、三氟甲氧基或喹啉基。
4.根据权利要求1~3任一所述的烷基醇衍生物的应用,其特征在于,所述烷基醇衍生物V的合成方法包括下述步骤:在溶剂中,60℃-80℃,烷基酮酰胺类衍生物IV、烷基卤代物、氢氧化钠与四丁基溴化铵反应1h~5h;
所述的烷基酮酰胺类衍生物IV、烷基卤代物、氢氧化钠与四丁基溴化铵的摩尔比为1:(1.0~3.0):(1.0~3.0):(0.05~0.2);
所述的溶剂为二氯甲烷、三氯甲烷、四氯化碳、四氢呋喃、***、甲苯、二甲苯、苯、环己烷、正己烷、二氧六环、乙腈、乙酸乙酯、N,N-二甲基甲酰胺、水或其中两种的混合溶剂;所述烷基酮酰胺类衍生物IV为具有如下结构的化合物:
其中,R1、R2同烷基醇衍生物V。
6.根据权利要求5所述的烷基醇衍生物的应用,其特征在于,所述烷基酮酰胺类化合物III的制备方法包括如下步骤:在有机溶剂中,0℃-80℃下,烷基酮酸、酰氯化试剂和N,N-二甲基甲酰胺先反应2~12小时,然后减压蒸馏除去溶剂和多余的酰氯化试剂,再加入有机溶剂和伯胺,0℃-120℃下反应0.5~12h;
所述的烷基酮酸、酰氯化试剂、N,N-二甲基甲酰胺、伯胺的摩尔比为(1.2~3.0):(1.3~20.0):(0.1~0.5):1;
所述的有机溶剂是极性或非极性溶剂。
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