CN111960962A - 一种镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法 - Google Patents
一种镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/38—Amides of thiocarboxylic acids
- C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C327/44—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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- 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
- Y02P20/584—Recycling of catalysts
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
本发明公开了一种镍催化的乙酰胺和硫代乙酰胺的α‑烷基化方法,包括如下步骤:以二价镍盐和膦配体原位生成的络合物为催化剂,以伯醇为烷基化试剂,在碱环境中,乙酰胺或硫代乙酰胺发生α‑烷基化反应,制得酰胺或硫代酰胺。乙酰胺和硫代乙酰胺的α‑烷基化反应,活性催化剂可以由二价镍盐和膦配体原位生成,避免了预先制备催化剂,操作简便,节省实验步骤和费用。
Description
技术领域
本发明属于有机合成技术领域,涉及一种镍催化的乙酰胺和硫代乙酰胺的α-烷基化反应,以制备各种类型酰胺和硫代酰胺化合物。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
酰胺在天然产物、生物活性物质、生命大分子中广泛存在,也是重要的化工产品。羧酸及羧酸衍生物与胺的反应是制备酰胺化合物的常用方法,但是结构复杂的羧酸及羧酸衍生物同样需要多步合成。因此,由简单乙酰基胺的α-烷基化反应来制备复杂结构的酰胺具有较高合成意义。传统的酰胺α-烷基化反应一般采用卤代烃作为烷基化试剂,然而这个过程有以下缺陷:(1)卤代烃多数有毒性,对环境不友好;(2)反应一般需要两步,首先在低温下加入强碱,使酰胺生成烯醇负离子,再慢慢加入卤代烃,实验操作繁琐;(3)反应产生大量无机盐副产物,后处理过程成本和环境压力大。
近年来,以醇为烷基化试剂,基于借氢策略的烷基化反应得到迅速发展,成为构建C-C键和C-N键的重要方法。在借氢机理中,伯醇在催化剂作用下脱氢生成醛,催化剂则变成金属氢化物;醛与羰基化合物(或者胺)发生缩合反应生成α,β-不饱和羰基化合物(或亚胺);然后催化剂氢化物对α,β-不饱和羰基化合物(或亚胺)进行氢化还原得到最终产物。与利用卤代烃为烷基化试剂的反应相比,借氢反应使用廉价无毒的醇为烷基化试剂,反应过程一步完成,反应的唯一副产物是水,因此是原子经济性高、环境友好的反应。目前已经有多种化合物通过此反应获得烷基化产物,如胺、酮、酯、腈和酰胺等。其中在各种羰基化合物中,酰胺的α-H酸性最弱,与伯醇脱氢之后的醛发生缩合时活性最低,因此烷基化难度较大。目前关于未活化酰胺的烷基化反应的论文报道有11篇,专利1项,这些文献报道的方法存在以下几个问题:(1)早期的反应采用基于Ir和Ru等贵金属的配合物催化剂价格昂贵,生产成本高,毒性较大,在医药分子合成时需要额外的纯化步骤,降低贵金属残留率,进一步提高了生产费用;(2)2016年以来出现了基于廉价金属Mn,Co和Ni的配合物催化剂,但是都需要比较高的反应温度(100-140℃)和较长的反应时间(15-24h),且产率普遍不高,以中等产率为主(40-80%),超过90%的不多;(3)无论是贵金属还是廉价金属催化剂,都需要预先制备金属络合物催化剂,有些催化剂稳定性差,合成困难,价格昂贵,增加了合成步骤和成本,不利于实际推广使用,因为别人需要自己合成催化剂,并且表征正确之后才能用于催化反应。(4)文献报道的反应都需使用耐压反应管,在氮气保护下或者在手套箱中完成加料操作,封管反应,实验过程较为繁琐,不适于较大规模的反应。
硫代酰胺类化合物本身具有多种生物活性,很多药物分子具有硫代酰胺结构。多肽的酰胺键进行硫代后,可以改变多肽的构象和活性。硫代酰胺也常用于合成含硫的杂环化合物,如噻唑、苯并噻唑、噻唑啉酮等。传统的硫代酰胺的合成方法是利用Lawesson’s试剂对酰胺进行硫化,异硫酸氰酯的加成反应,芳基醛/酮与胺、硫单质的Willgerodt-Kindler反应等。这些方法存在着原子经济性低、底物类型有限等问题。
发明内容
为了解决现有技术中存在的技术问题,本发明的目的是提供一种镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,不仅能够克服现有过渡金属催化乙酰胺α-烷基化的缺点,而且具有环境友好、操作简单、反应高效、底物适用性广、条件温和、产率较高等优点。
为解决以上技术问题,本发明的以下一个或多个实施例提供了如下技术方案:
一种镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,包括如下步骤:
以二价镍盐和膦配体原位生成的络合物为催化剂,以伯醇为烷基化试剂,在碱性环境中,乙酰胺或硫代乙酰胺发生α-烷基化反应,制得酰胺或硫代酰胺。
与现有技术相比,本发明的以上一个或多个技术方案取得了以下有益效果:
乙酰胺和硫代乙酰胺的α-烷基化反应,活性催化剂可以由二价镍盐和膦配体原位生成,避免了预先制备催化剂,操作简便,节省实验步骤和费用。
使用普通回流反应装置,不需要封管反应,不需要在手套箱中操作,适宜放大规模生产;采用廉价的镍做催化剂,催化剂用量低,且避免使用昂贵且毒性较高的贵金属,进一步节省了成本;伯醇做为烷基化试剂,相对廉价易得,无毒或低毒,副产物只有水,对环境友好;产率非常高、底物适用范围广。
具体实施方式
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本发明的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
一种镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,包括如下步骤:
以二价镍盐和膦配体原位生成的络合物为催化剂,以伯醇为烷基化试剂,在碱环境中,乙酰胺或硫代乙酰胺发生α-烷基化反应,制得酰胺或硫代酰胺。
在一些实施例中,镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,具体包括如下步骤:搅拌下,依次将镍盐、膦配体、碱、伯醇、乙酰胺或硫代乙酰胺加入到溶剂中,加热反应。
在一些实施例中,所述乙酰胺为R2和R3彼此独立选自H、C1-C30烷基、含一个或多个杂原子的C1-C30的烷基、C6-C30芳基、单或多取代芳基、杂环芳基,或者R2、R3与和它们相连的N原子形成环,所述环中可包含一个或多个杂原子。
本发明涉及的反应可以用以下反应式表示:
在一些实施例中,所述二价镍盐为醋酸镍、溴化镍、三氟甲磺酸镍或乙酰丙酮镍中的一种或多种的混合物。
在一些实施例中,所述膦配体为烷基膦配体。
进一步的,所述烷基膦配体为三叔丁基膦、三环己基膦或三丁基膦中的一种或多种的混合物。经过试验验证,烷基膦配体与二价镍形成的络合物催化活性最高,产率最高。
活性催化剂可以由廉价的二价镍盐和市售膦配体原位生成,避免了预先制备催化剂,操作简便,节省实验步骤和费用。
制得的催化剂的活性非常高,用量仅为0.5%,而产率非常高,系列实施案例中的产率均大于90%。
以廉价金属镍为催化剂,避免了以往方法中贵金属催化剂成本高和毒性高的弊端,降低了成本和对环境的污染,有很好的应用推广价值。
在一些实施例中,二价镍盐与膦配体的摩尔比为1:1.2~2.2。优选的,二价镍盐与膦配体的摩尔比为1:2。
进一步的,二价镍盐与伯醇的摩尔比为1:50~250。优选的,二价镍盐与原料伯醇的摩尔比为1:200。
进一步的,伯醇与乙酰胺或硫代乙酰胺的摩尔比为1:1~2。优选的,伯醇与乙酰胺或硫代乙酰胺的摩尔比为1:1.5。
在一些实施例中,所述碱环境由叔丁醇钾提供。经过试验发现,当采用此碱时,能够使产物具有更高的产率。
进一步的,碱与伯醇的摩尔比为0.8~2:1。优选的,碱与伯醇的摩尔比为1:1。
在一些实施例中,α-烷基化反应所处的溶剂环境为1,4-二氧六环、正辛烷、甲苯中的一种或多种的混合物。优选的,α-烷基化反应所处的溶剂环境为1,4-二氧六环。在此溶剂中,能够使得产物具有较高的产率。
在一些实施例中,α-烷基化反应的反应温度为80~90℃,反应时间12~18小时。
在一些实施例中,α-烷基化反应结束后,还包括利用硅胶柱层析纯化产品的步骤。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案,以下将结合具体的实施例详细说明本发明的技术方案。
优化反应条件的标准实验步骤,如下:
在充满氮气的手套箱中,搅拌条件下,向10mL的史莱克管加入镍盐、三叔丁基膦、溶剂(0.6mL)、碱(1mmol)、苯甲醇(1mmol,108.1mg)和N,N-二甲基乙酰胺(1.5mmol,130.5mg)。反应管封口,在80℃油浴中搅拌加热12小时。反应停止后,冷却,反应液直接加入到硅胶柱,用石油醚和乙酸乙酯(体积比2:1)洗脱,得纯净产品,无色油状液体,计算产率,见表1。
表1
由表1可知,效果较优的溶剂为1,4-二氧六环,效果较优的碱为叔丁醇钾,较为重要的是,叔丁醇钾、1,4-二氧六环和三叔丁基膦配合使用时,可以获得更高的产率。
实施例1:制备N,N-二甲基-3-苯基丙酰胺
室温搅拌条件下,向50mL的圆底烧瓶中加入醋酸镍(17.7mg,0.1mmol,0.5mol%)、三叔丁基膦(40.5mg,0.2mmol,1mol%)、叔丁醇钾(20mmol,2.24g)、苯甲醇(20mmol,2.16g)、N,N-二甲基乙酰胺(30mmol,2.61g)和1,4-二氧六环(24mL),圆底烧瓶安装球形冷凝管,并在冷凝管上端插一个空的气球,以防止空气和水分进入,并能指示体系压力。反应需要剧烈搅拌,在80℃油浴中加热12小时。反应停止后,冷却,加入10mL水淬灭反应,用乙酸乙酯萃取三次(3x 15mL),有机相合并,无水硫酸钠干燥,过滤,滤液浓缩后加入到硅胶柱,用石油醚和乙酸乙酯(体积比2:1)洗脱,得纯净产品,无色油状液体,产率99%。核磁和高分辨质谱数据如下:
1H NMR(400MHz,CDCl3)δ=7.30-7.26(m,2H),7.23-7.17(m,3H),3.00-2.92(m,8H,overlapping signals of NMe2 and CH2),2.61(t,J=8.0Hz,2H).
13C NMR(100MHz,CDCl3)δ=172.3,141.6,128.54,128.50,126.2,37.2,35.5,35.4,31.5.
HRMS(ESI):Calcd for C11H15NO:[M+H]+:178.1232;found:178.1197.
实施例2:制备N,N-二甲基-3-(对甲苯基)丙酰胺
室温搅拌条件下,向50mL的圆底烧瓶中加入醋酸镍(17.7mg,0.1mmol,0.5mol%)、三叔丁基膦(40.5mg,0.2mmol,1mol%)、叔丁醇钾(20mmol,2.24g)、对甲基苯甲醇(20mmol,2.44g)、N,N-二甲基乙酰胺(30mmol,2.61g)和1,4-二氧六环(24mL),圆底烧瓶安装球形冷凝管,并在冷凝管上端插一个空的气球,以防止空气和水分进入,并能指示体系压力。反应需要剧烈搅拌,在80℃油浴中加热12小时。反应停止后,冷却,加入10mL水淬灭反应,用乙酸乙酯萃取三次(3x 15mL),有机相合并,无水硫酸钠干燥,过滤,滤液浓缩后加入到硅胶柱,用石油醚和乙酸乙酯(体积比2:1)洗脱,得纯净产品,无色油状液体,产率99%。核磁和高分辨质谱数据如下:
1H NMR(400MHz,CDCl3)δ=7.13-7.08(m,4H),2.94-2.91(m,8H,overlappingsignals of NMe2 and CH2),2.59(t,J=8.0Hz,2H),2.31(s,3H).
13C NMR(100MHz,CDCl3)δ=172.3,138.5,135.6,129.2,128.3,37.2,35.5,35.4,31.0,21.1.
HRMS(ESI):Calcd for C12H17NO:[M+Na]+:214.1208;found:214.1205.
实施例3:制备N,3-二苯基丙酰胺
室温搅拌条件下,向50mL的圆底烧瓶中加入醋酸镍(17.7mg,0.1mmol,0.5mol%)、三叔丁基膦(40.5mg,0.2mmol,1mol%)、叔丁醇钾(20mmol,2.24g)、苯甲醇(20mmol,2.16g)、乙酰苯胺(30mmol,4.05g)和1,4-二氧六环(24mL),圆底烧瓶安装球形冷凝管,并在冷凝管上端插一个空的气球,以防止空气和水分进入,并能指示体系压力。反应需要剧烈搅拌,在80℃油浴中加热12小时。反应停止后,冷却,加入10mL水淬灭反应,用乙酸乙酯萃取三次(3x 15mL),有机相合并,无水硫酸钠干燥,过滤,滤液浓缩后加入到硅胶柱,用石油醚和乙酸乙酯(体积比4:1)洗脱,得纯净产品,白色固体,产率98%。核磁和高分辨质谱数据如下:
1H NMR(400MHz,CDCl3)δ=7.45-7.43(m,2H),7.32-7.27(m,4H),7.24-7.18(m,4H),7.11-7.07(m,1H),3.05(t,J=7.6Hz,2H),2.66(t,J=8.0Hz,2H).
13C NMR(100MHz,CDCl3)δ=170.5,140.8,137.9,129.1,128.8,128.5,126.5,124.4,120.0,39.6,31.7.
HRMS(ESI):Calcd for C15H15NO:[M+Na]+:248.1052;found:248.1013.
实施例4:制备N-苯基癸酰胺
室温搅拌条件下,向50mL的圆底烧瓶中加入醋酸镍(17.7mg,0.1mmol,0.5mol%)、三叔丁基膦(40.5mg,0.2mmol,1mol%)、叔丁醇钾(20mmol,2.24g)、正辛醇(20mmol,2.60g)、乙酰苯胺(30mmol,4.05g)和1,4-二氧六环(24mL),圆底烧瓶安装球形冷凝管,并在冷凝管上端插一个空的气球,以防止空气和水分进入,并能指示体系压力。反应需要剧烈搅拌,在80℃油浴中加热12小时。反应停止后,冷却,加入10mL水淬灭反应,用乙酸乙酯萃取三次(3x 15mL),有机相合并,无水硫酸钠干燥,过滤,滤液浓缩后加入到硅胶柱,用石油醚和乙酸乙酯(体积比4:1)洗脱,得纯净产品,白色固体,产率96%。核磁和高分辨质谱数据如下:
1H NMR(400MHz,CDCl3)δ=7.52-7.50(m,2H),7.33-7.29(m,2H),7.15-7.10(m,2H),2.35(t,J=7.6Hz,2H),1.76-1.69(m,2H),1.34-1.26(m,12H),0.89-0.86(m,3H).
13C NMR(100MHz,CDCl3)δ=171.5,129.1,124.3,119.9,38.0,32.0,29.6,29.5,29.43,29.42,25.8,22.8,14.2.
HRMS(ESI):Calcd for C16H25NO:[M+Na]+:270.1834;found:270.1807.
实施例5:制备N-甲基-N,3-二苯基丙酰胺
室温搅拌条件下,向50mL的圆底烧瓶中加入醋酸镍(17.7mg,0.1mmol,0.5mol%)、三叔丁基膦(40.5mg,0.2mmol,1mol%)、叔丁醇钾(20mmol,2.24g)、苯甲醇(20mmol,2.16g)、N-甲基-N-乙酰基苯胺(30mmol,4.48g)和1,4-二氧六环(24mL),圆底烧瓶安装球形冷凝管,并在冷凝管上端插一个空的气球,以防空气和水分进入,并能指示体系压力。反应需要剧烈搅拌,在80℃油浴中加热12小时。反应停止后,冷却,加入10mL水淬灭反应,用乙酸乙酯萃取三次(3x 15mL),有机相合并,无水硫酸钠干燥,过滤,滤液浓缩后加入到硅胶柱,用石油醚和乙酸乙酯(体积比4:1)洗脱,得纯净产品,黄色油状液体,产率98%。核磁和高分辨质谱数据如下:
1H NMR(400MHz,CDCl3)δ=7.39-7.30(m,3H),7.24-7.16(m,3H),7.07-7.01(m,4H),3.25(s,3H),2.91(t,J=8.0Hz,2H),2.37(t,J=8.0Hz,2H).
13C NMR(100MHz,CDCl3)δ=172.3,144.0,141.3,129.8,128.5,128.4,127.8,127.4,126.1,37.4,36.1,31.9.
HRMS(ESI):Calcd for C16H17NO:[M+Na]+:262.1208;found:262.1182.
实施例6:制备N-苯丙酰基吗啉
室温搅拌条件下,向50mL的圆底烧瓶中加入醋酸镍(17.7mg,0.1mmol,0.5mol%)、三叔丁基膦(40.5mg,0.2mmol,1mol%)、叔丁醇钾(20mmol,2.24g)、苯甲醇(20mmol,2.16g)、乙酰基吗啉(30mmol,3.87g)和1,4-二氧六环(24mL),圆底烧瓶安装球形冷凝管,并在冷凝管上端插一个空的气球,以防空气和水分进入,并能指示体系压力。反应需要剧烈搅拌,在80℃油浴中加热12小时。反应停止后,冷却,加入10mL水淬灭反应,用乙酸乙酯萃取三次(3x 15mL),有机相合并,无水硫酸钠干燥,过滤,滤液浓缩后加入到硅胶柱,用石油醚和乙酸乙酯(体积比4:1)洗脱,得纯净产品,白色固体,产率98%。核磁和高分辨质谱数据如下:
1H NMR(400MHz,CDCl3)δ=7.30-7.26(m,2H),7.22-7.18(m,3H),3.61(m,4H),3.51-3.49(m,2H),3.36-3.33(m,2H),2.97(t,J=8.0Hz,2H),2.61(t,J=8.0Hz,2H).
13C NMR(100MHz,CDCl3)δ=170.9,141.2,128.6,128.5,126.4,46.1,42.0,34.9,31.7.
HRMS(ESI):Calcd for C13H17NO2:[M+Na]+:242.1157;found:242.1136.
实施例7:制备N,N-二甲基-3-苯基丙硫酰胺
室温搅拌条件下,向10mL的圆底烧瓶中加入醋酸镍(7.07mg,0.04mmol,2.0mol%)、三叔丁基膦(16.2mg,0.08mmol,4mol%)、叔丁醇钾(2mmol,224mg)、苯甲醇(2mmol,216mg)、N,N-二甲基硫代乙酰胺(3mmol,310mg)和1,4-二氧六环(3mL),圆底烧瓶安装球形冷凝管,并在冷凝管上端插一个空的气球,以防空气和水分进入,并能指示体系压力。反应需要剧烈搅拌,在80℃油浴中加热12小时。反应停止后,冷却,加入5mL水淬灭反应,用乙酸乙酯萃取三次(3x 5mL),有机相合并,无水硫酸钠干燥,过滤,滤液浓缩后加入到硅胶柱,用石油醚和乙酸乙酯(体积比4:1)洗脱,得纯净产品,黄色油状液体,产率96%。核磁和高分辨质谱数据如下:
1H NMR(400MHz,CDCl3)δ=7.31-7.27(m,2H),7.24-7.21(m,3H),3.45(s,3H),3.14(s,3H),3.13-3.01(m,2H),3.08-3.04(m,2H).
13C NMR(100MHz,CDCl3)δ=203.3,140.8,128.7,128.6,126.5,45.0,44.7,41.6,35.8.
HRMS(ESI):Calcd for C11H15NS:[M+Na]+:216.0823;found:216.0801.
实施例8:制备N,N-二甲基-3-(萘-2-基)丙烷硫代酰胺
室温搅拌条件下,向10mL的圆底烧瓶中加入醋酸镍(7.08mg,0.4mmol,2.0mol%)、三叔丁基膦(16.2mg,0.8mmol,4mol%)、叔丁醇钾(2mmol,224mg)、2-萘甲醇(2mmol,316mg)、N,N-二甲基硫代乙酰胺(3mmol,310mg)和1,4-二氧六环(3mL),圆底烧瓶安装球形冷凝管,并在冷凝管上端插一个空的气球,以防空气和水分进入,并能指示体系压力。反应需要剧烈搅拌,在80℃油浴中加热12小时。反应停止后,冷却,加入5mL水淬灭反应,用乙酸乙酯萃取三次(3x 5mL),有机相合并,无水硫酸钠干燥,过滤,滤液浓缩后加入到硅胶柱,用石油醚和乙酸乙酯(体积比4:1)洗脱,得纯净产品,黄色油状液体,产率95%。核磁和高分辨质谱数据如下:
1H NMR(400MHz,CDCl3)δ=7.82-7.77(m,3H),7.68-7.67(m,1H),7.45(qd,J=1.6Hz,2H),7.37(dd,J=1.6Hz,1H),3.49(s,3H),3.31-3.27(m,2H),3.17-3.13(m,5H).
13C NMR(100MHz,CDCl3)δ=203.3,138.3,133.7,128.3,127.8,127.6,127.2,126.7,126.2,125.6,45.0,44.8,41.7,36.0.
HRMS(ESI):Calcd for C15H17NS:[M+Na]+:266.0980;found:266.0958。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,其特征在于:包括如下步骤:
以二价镍盐和膦配体原位生成的络合物为催化剂,以伯醇为烷基化试剂,在碱环境中,乙酰胺或硫代乙酰胺发生α-烷基化反应,制得酰胺或硫代酰胺。
2.根据权利要求1所述的镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,其特征在于:镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,具体包括如下步骤:搅拌下,依次将镍盐、膦配体、碱、伯醇、乙酰胺或硫代乙酰胺加入到溶剂中,加热反应。
5.根据权利要求1所述的镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,其特征在于:二价镍盐与膦配体的摩尔比为1:1.2~2.2;
优选的,二价镍盐与膦配体的摩尔比为1:2;
进一步的,二价镍盐与伯醇的摩尔比为1:50~250;
优选的,二价镍盐与原料伯醇的摩尔比为1:200。
进一步的,伯醇与乙酰胺或硫代乙酰胺的摩尔比为1:1~2;
优选的,伯醇与乙酰胺或硫代乙酰胺的摩尔比为1:1.5。
6.根据权利要求1所述的镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,其特征在于:所述碱环境由叔丁醇钾提供。
7.根据权利要求1所述的镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,其特征在于:碱与伯醇的摩尔比为0.8~2:1;
优选的,碱与伯醇的摩尔比为1:1。
8.根据权利要求1所述的镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,其特征在于:α-烷基化反应所处的溶剂环境为1,4-二氧六环、甲苯、正辛烷中的一种或多种的混合物;
优选的,α-烷基化反应所处的溶剂环境为1,4-二氧六环。
9.根据权利要求1所述的镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,其特征在于:α-烷基化反应的反应温度为80~90℃,反应时间12~18小时。
10.根据权利要求1所述的镍催化的乙酰胺和硫代乙酰胺的α-烷基化方法,其特征在于:α-烷基化反应结束后,还包括利用硅胶柱层析纯化产品的步骤。
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JAGANNATH RANA等: "Manganese-catalyzed direct C–C coupling of α-C–H bonds of amides and esters with alcohols α-C–H bonds of amides and esters with alcohols", 《DALTON TRANS.》 * |
NICKLAS DEIBL等: "General and Mild Cobalt-Catalyzed C‑Alkylation of Unactivated Amides and Esters with Alcohols", 《J. AM. CHEM. SOC.》 * |
S.P.MIDYA等: "Ni‐Catalyzed ‐Alkylation of Unactivated Amides and Esters with Alcohols by Hydrogen", 《CHEMSUSCHEM 》 * |
SUBRATA CHAKRABORTY等: "Manganese-Catalyzed α‑Alkylation of Ketones, Esters, and Amides Using Alcohols", 《ACS CATAL.》 * |
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