还原胺化知识
还原胺化反应的应用及其机理研究
还原胺化反应的应用及其机理研究胺化反应的应用及其机理研究
作为一种十分重要的化学反应，胺化反应在化学工业中有广泛应用，如用来制
备有机延迟剂、合成着色剂。
本文将对胺化反应的应用和机理进行深入研究，为此有效应用以及进一步的研究提供参考。
1. 胺化反应的应用
胺化反应是一种化学反应，主要是在胺基与有机物中的碳原子或其他碳基之间
新生成胺基。
其中，植物提取物中常见的胺化反应：氨基酸到酒精或醛类衍生物之间的反应，也主要用于制备有机延迟剂，如氨基氯元素。
此外，还可用于合成着
色剂，例如由氨基酸和酚类衍生物经胺化反应合成的着色剂，可以更好地改善食品的感官质量，使食物更加色彩缤纷。
2. 胺化反应的机理
胺化反应的机理主要是由胺基和有机物的碳原子的相互作用，从而形成一个芳
香族键，并且将胺基与有机物中的烃类或其他衍生物之间形成叉型分子结构。
在此反应中，活性H应用于驱动反应，成为衍生物生成胺基而非原子的活力试剂。
值得注意的是，胺基有其独立的酸性或碱性，往往会影响其与有机物之间的反应机理。
3. 结论
总的来说，准确的应用和掌握胺化反应的机理，将有助于更好地运用胺化反应，以满足相关新的应用需求。
此外，对胺化反应的机理的深入研究也有助于我们正确理解胺化反应所发生的物理化学过程，从而使我们更好地掌握胺化反应。
还原胺化
一.还原胺化还原胺化主要有一般化合物的还原法及直接的还原胺化法。
1.C-N化合物还原法硝基化合物、亚硝基化合物、肟、腈、酰胺、偶氮化合物、氧化偶氮化合物、氢化偶氮化合物等均可经还原得到胺类。
(1).硝基及亚硝基的还原硝基和亚硝基化合物的还原较易进行，主要有化学还原法和催化加氢还原法。
化学还原法根据催化剂的不同，又分为铁屑还原，含硫化合物的还原，碱性介质中的锌粉还原等。
铁屑还原法的适用范围较广，凡能与铁泥分离的芳胺皆可采用此法，其还原过程包括还原反应、还原产物的分离与精制、芳胺废水与铁泥处理等几个基本步骤。
对于容易随水蒸气蒸出的芳胺如苯胺、邻（对）甲苯胺、邻（对）氯苯胺等都可采用水蒸气蒸馏法将产物与铁泥分离；对于易溶于水且可蒸馏的芳胺如间（对）苯二胺、2，4-二氨基甲苯等，可用过滤法先除去铁泥，再浓缩滤液，进行真空蒸馏，得到芳胺；能溶于热水的芳胺如邻苯二胺、邻氨基苯酚、对氨基苯酚等，用热过滤法与铁泥分离，冷却滤液即可析出产物；对含有磺基或羧基等水溶性基团的芳胺，如1-氨基萘-8-磺酸（周位酸）、1-氨基萘-5-磺酸等，可将还原产物中和至碱性，使氨基磺酸溶解，滤去铁泥，再用酸化或盐析法析出产品，难溶于水而挥发性又小的芳胺，例如1-萘胺，在还原后用溶剂将芳胺从铁泥中萃取出来。
铁屑还原法中产生大量含胺废水，必须进行处理、回收。
例如在硝基苯用铁屑还原过程中会产生大量含苯胺废水（约含4%苯胺），一部分可加入到还原锅中循环使用，其余的要先用硝基苯萃取。
萃取后含苯胺的硝基苯可作为还原的原料使用；废水中的苯胺和硝基苯的含量分别降为0.2%和0.1%以下。
此后还必须经过生化处理，才可排放。
铁泥的利用途径之一是制铁红颜料。
含硫化合物的还原主要包括硫化碱类，如硫化钠、硫氢化铵、多硫化铵，这类反应称为齐宁反应(Zinin)，该反应比较缓和，可使多硝基化合物中的硝基选择性的部分还原，或只还原硝基偶氮化合物中的硝基，而保留偶氮基，并应用于从硝基化合物获得的不溶于水的胺类。
苯基丙酮还原胺化反应的学习要点
苯基丙酮还原胺化反应的学习要点还原胺化的定义：还原性胺化，也称为氨化。
生成的胺化合物的反应。
先胺化再还原，是还原胺化后的产物，所以叫还原胺化。
还原胺化反应里酮或者醛跟胺反应出来的是R1-CH=N-R2。
胺是氨基（-NH2）取代烃上的H原子以后的产物，如CH3CH2-NH2，也可以看成是烃基取代了氨分子中的氢原子。
烃基取代了氨分子中的1个氢原子叫伯胺，甲胺是伯胺的一种；烃基取代了氨分子中的2个氢原子叫叫亚胺如CH3CH2-NH-CH3。
苯基丙酮不是脂肪酮，它属于芳香酮，因为含有苯环，可以发生Leuckart反应（甲酸的铵盐与醛酮通过还原胺化形成胺）苯基丙酮还原胺化的方法很多，比如Clemmensen还原法或者黄鸣龙还原法，即锌汞齐、浓盐酸加热回流得到目标产物，或者先与水合肼反应生成腙，然后在碱的作用下分解得到目标产物，还可以将底物转化为缩硫酮后，用活性镍脱硫得到目标产物。
甲基苯丙胺（MAM）合成方法有很多，方法的选择取决于起始原料，现在比较流行的是苯基丙酮（P2P）为起始原料。
甲基苯丙胺（MAM）的合成还有用EP PEP 为原料将素的羟基还原氢化就可得到MA。
EP与PEP均为具有手性碳的光学异构体。
合成过程中手性碳不参于反应。
因此产物仍具有光学活性。
而P2P的羰基是平面的与氨或甲胺加成时可在上下方同时进行，几率相同，下面有扣扣，需要可以加，所以产物是外消旋体。
P2P为起始原料的合成MAM的方法最常用的有以下几种：苯基丙酮-胺化西佛碱-反应的亚胺-稳定成胺-产品。
这种方法的优点在于产量高.稳定.速度快。
缺点在于设备要求比较高.带有点胺味。
苯基丙酮-溴代还原-产品。
这种方法的优点在与设备简单.东西比较好。
缺点太明显了，产量低.操作很复杂纯手工打造累人。
苯基丙酮-氧化物-产品。
这就是传说中的一锅法。
优点太多，由于反应时没什么要求，通常很简单。
对设备要求可以说是零，也就是在有原料的时候可以不借用任何设备只要几个简单的杯子就可以成产品。
还原胺化 用盐酸盐
还原胺化用盐酸盐
摘要：
1.还原胺化的概念
2.盐酸盐在还原胺化反应中的作用
3.还原胺化反应的实验操作
4.反应过程中的注意事项
5.还原胺化反应的应用领域
正文：
还原胺化是一种有机合成反应，通过在胺上添加一个氢原子，从而生成一个新的化合物。
在这个过程中，盐酸盐起到至关重要的作用，它能够调节反应的酸碱度，促进反应的进行。
盐酸盐在还原胺化反应中的作用主要体现在以下两个方面：首先，盐酸盐作为酸性物质，能够中和胺的碱性，使得胺更容易接受氢原子。
其次，盐酸盐还能够作为质子受体，与胺形成盐，从而使胺更容易失去质子，进而发生还原胺化反应。
在实验操作过程中，首先需要将胺和盐酸盐混合，然后加热反应。
在反应过程中，需要密切注意反应的酸碱度，以及反应的温度，避免反应过快或过热，导致副反应的产生。
在还原胺化反应中，还有一些需要注意的事项。
例如，胺的选取要合适，不能选用太活泼或太不活泼的胺，否则反应效果会受到影响。
此外，盐酸盐的浓度也需要严格控制，浓度过高或过低都会影响反应的效果。
还原胺化反应在有机合成领域有着广泛的应用，例如在药物合成、香料合成等方面都有重要的应用。
通过调节盐酸盐的浓度、温度等条件，可以有效地控制反应的进行，从而获得理想的产物。
总的来说，还原胺化是一种重要的有机合成反应，盐酸盐在其中的作用关键而重要。
还原胺化反应条件
还原胺化反应条件1 胺化反应胺化反应是一种化学反应，它由一种化合物与一种或多种胺发生氨基取代反应。
它是一种重要的化学反应，在有机合成中发挥着重要作用。
胺化反应通常与醇、碱和碳酸酯等多种有机物反应，可以产生活性元素，使这些反应物发生进一步的有机反应。
2 条件胺化反应可以在醇与胺反应，烃与胺反应和醇与酯反应等条件下进行。
由于胺化反应涉及到胺的氨基取代，因此，在实施胺化反应时，应采用简单的反应操作，使反应更加有效和高效，以确保反应产物的纯度和分离性。
一般情况下，要能够取得显著的氨基取代反应，需要考虑以下几个还原条件：- 静置反应时间：控制反应时间是很重要的，过长的反应时间可能会导致反应物不完全反应，胺化反应一般在几小时内完成。
- 反应温度：胺化反应的最佳反应温度一般在65℃～80℃。
- 胺与醇的重量比：胺与醇的重量比应根据反应条件来定。
一般来说胺的重量比应较大，但不少于1:1的重量比。
- 反应介质：反应介质必须无水或低含水量，可以使用回流烷。
- 添加剂：胺化反应中，典型的催化剂有里夫那酸、醋酸钠或过硫酸钠。
3 还原为了还原胺化反应，通常需要增加反应时间和反应温度，并增加反应物的重量比，或改变反应介质，或者添加催化剂。
除此之外，有些反应除了胺之外还需要用到其他物质，比如甲酸。
因此，在反应中加入适量的甲酸，可以进一步促进反应的发生。
4 总结胺化反应是一种经常使用的有机反应，需要在静置时间、反应温度、反应物比例、反应介质以及反应剂的选择等方面考虑的要素，控制这些要素正确来获得正确的反应产物。
要还原胺化反应，一般需要增加反应时间和反应温度，增加反应物比例，或改变反应介质，或添加催化剂。
还原胺化
一.还原胺化还原胺化主要有一般化合物的还原法及直接的还原胺化法。
1.C-N化合物还原法硝基化合物、亚硝基化合物、肟、腈、酰胺、偶氮化合物、氧化偶氮化合物、氢化偶氮化合物等均可经还原得到胺类。
(1).硝基及亚硝基的还原硝基和亚硝基化合物的还原较易进行，主要有化学还原法和催化加氢还原法。
化学还原法根据催化剂的不同，又分为铁屑还原，含硫化合物的还原，碱性介质中的锌粉还原等。
铁屑还原法的适用范围较广，凡能与铁泥分离的芳胺皆可采用此法，其还原过程包括还原反应、还原产物的分离与精制、芳胺废水与铁泥处理等几个基本步骤。
对于容易随水蒸气蒸出的芳胺如苯胺、邻（对）甲苯胺、邻（对）氯苯胺等都可采用水蒸气蒸馏法将产物与铁泥分离；对于易溶于水且可蒸馏的芳胺如间（对）苯二胺、2，4-二氨基甲苯等，可用过滤法先除去铁泥，再浓缩滤液，进行真空蒸馏，得到芳胺；能溶于热水的芳胺如邻苯二胺、邻氨基苯酚、对氨基苯酚等，用热过滤法与铁泥分离，冷却滤液即可析出产物；对含有磺基或羧基等水溶性基团的芳胺，如1-氨基萘-8-磺酸（周位酸）、1-氨基萘-5-磺酸等，可将还原产物中和至碱性，使氨基磺酸溶解，滤去铁泥，再用酸化或盐析法析出产品，难溶于水而挥发性又小的芳胺，例如1-萘胺，在还原后用溶剂将芳胺从铁泥中萃取出来。
铁屑还原法中产生大量含胺废水，必须进行处理、回收。
例如在硝基苯用铁屑还原过程中会产生大量含苯胺废水（约含4%苯胺），一部分可加入到还原锅中循环使用，其余的要先用硝基苯萃取。
萃取后含苯胺的硝基苯可作为还原的原料使用；废水中的苯胺和硝基苯的含量分别降为0.2%和0.1%以下。
此后还必须经过生化处理，才可排放。
铁泥的利用途径之一是制铁红颜料。
含硫化合物的还原主要包括硫化碱类，如硫化钠、硫氢化铵、多硫化铵，这类反应称为齐宁反应(Zinin)，该反应比较缓和，可使多硝基化合物中的硝基选择性的部分还原，或只还原硝基偶氮化合物中的硝基，而保留偶氮基，并应用于从硝基化合物获得的不溶于水的胺类。
还原氨基化
还原氨基化还原氨基化是一种重要的有机反应，在化学合成中有广泛的应用。
它是指在反应中还原胺的氮原子上的氨基，通常使用还原剂将氮上的氨基还原成亚胺基。
本文将介绍还原氨基化的基本原理、反应机理、应用等方面的内容。
还原氨基化是一种有机化学中的重要反应。
在这种反应中，胺的氮上的氨基通过还原剂还原成了亚胺基。
还原剂的选择通常是亲电性较弱的试剂，如氢气、金属碱金属醇ates 、氢氧化钠/钾、硼氢化钠/钾等。
这些还原剂可以直接作用于氮上的氨基，并将其还原为亚胺基，使得减少的电子被转移到邻近的碳原子上。
一般还原氨基化是通过还原剂将氮上的氨基还原成亚胺基。
当胺与还原剂进行反应时，由于还原剂的亲电性较弱，所以其不能直接攻击氮上的氨基，因此必须先发生负载的过程。
在胺和还原剂反应中，还原剂先负载在胺的氮上形成N-依附物。
由于N-依附物中的氮上的孤对电子对会与还原剂之间建立较强的σ键，因此可以加快其反应。
这样，还原剂就能直接作用于氮上的氨基，并将其还原为亚胺基。
还原剂还可以转移氮上氨基上的电子到其邻近碳原子上，从而形成甲基/亚甲基/亚硝基等官能团。
还原氨基化在有机化学合成中有广泛的应用，可以用于制备多种具有生物活性的分子。
下面介绍几个具体的例子。
1. 含醛的还原胺化反应：还原胺化反应是将醛和胺反应生成亚胺的一种重要反应。
该反应的前身是高里仁还原反应，被广泛用于各种药物分子的合成中。
如对月季糖、头孢克肟等合成中均采用该反应。
2. 氧膦酸多缩醛的还原胺化反应：氧膦酸多缩醛是一类特殊的羧酸衍生物，具有很高的生物活性。
还原胺化反应可以有效地将氧膦酸多缩醛等官能团转化为亚胺基，从而构建出具有生物活性的药物分子。
3. 羟甲基庚环素的还原反应：羟甲基庚环素是一种具有广泛应用的药物分子，其合成通常需要采用还原反应。
例如，羟甲基庚环素可以通过还原氨基化反应生成。
总之，还原氨基化反应在有机合成中具有重要的应用价值，能够合成许多具有生物活性的分子。
苯基丙酮还原胺化操作工艺的概述与参考
一：苯基丙酮还原胺化介绍：还原胺化是氨与醛或酮缩合以形成亚胺的过程，其随后还原成胺。
利用还原胺化从1-苯基-2-丙酮和氨生产苯丙胺。
氨与醛和酮反应形成称为亚胺的化合物（与消除水的缩合反应）。
第一步是亲核加成羰基，随后快速质子转移。
所得产物，一种有时称为甲醇胺的hemiaminal通常是不稳定的，不能分离。
发生第二反应，其中水从hemiaminal中除去并形成亚胺。
胺随后的还原胺通常通过用氢气和合适的氢化催化剂处理或用铝 - 汞汞齐或通过氰基硼氢化钠处理来完成。
二：苯基丙酮催化氢化还原胺化介绍：通过醛或酮和氨的混合物的催化氢化进行还原胺化导致存在过量氨时伯胺的优势。
应使用至少五当量的氨; 较小的量导致形成更多的仲胺。
重要的副反应使还原胺化方法复杂化。
当伯胺开始积聚时，它可以与中间体亚胺反应形成还原成仲胺的亚胺。
伯胺也可以与起始酮缩合，得到还原成仲胺的亚胺。
通过在反应介质中使用大量过量的氨，可以使该副反应最小化。
另一个可能的副反应是将羰基还原成羟基（例如，苯基-2-丙酮可以还原成苯基-2-丙醇）。
使用苯基-2-丙酮，甲醇溶剂，阮内镍和在轻微过压下通过溶液鼓泡的氨和氢气的混合物在室温还原胺化下对反应介质进行分析，并将苯丙胺产物经反复结晶。
（fn.1）由于苯丙胺中少量的杂质，其中以高得多的量发生杂质的反应混合物用于分析。
发现的主要杂质是苯丙胺和苄基甲基酮（苯基-2-丙酮），苄基甲基酮苯基异丙基亚胺的席夫碱（亚胺）。
该化合物是未被氢化的苯基-2-丙酮和苯丙胺的缩合产物。
还原胺联通通常不会产生非常高的伯胺产率，尽管报告苯丙胺的产率高。
阮内镍在这方面特别有用，特别是在升高的温度和压力下。
用阮内镍在低压下进行的还原胺化作用通常不是非常成功，除非使用大量的催化剂。
应该注意的是，在贵金属的还原胺化中，铵盐的存在是必需的; 在没有铵盐的情况下，催化剂被灭活。
亚胺的分离及其随后的还原有时被报道比还原胺化更有效，但是通常难以获得高产量的亚胺和不稳定性，反对该方法。
还原胺化相关机理与反应
还原胺化（reductive Amination）1.定义：胺和羰基化合物缩合得到亚胺，然后通过还原剂（常用的有NaCNBH3，NaBH(OAc)3等）还原生成相应的胺的反应。
2.反应机理：3.主要特点：Borch还原或者还原烷基；能够有效的将醛或者酮转化成胺；席夫碱来源于羰基和氨基，然后由氢供体还原成胺；对于迟钝反应，如含弱亲电羰基、亲核胺、空间拥挤的反应中心，通常需要添加分子筛或路易斯酸；对于反应性好的胺，容易形成席夫碱，直接还原胺化提高了效率；对于低反应性的胺，在一般条件下很难形成席夫碱。
4.优势：操作简单，方便；能形成伯胺、仲胺、叔胺。
5.经典反应：1.催化氢化；2.金属氢化物；3.甲酸-Leuckart-Wallach 反应；4.其他还原剂如硼烷、锡烷以及不对称催化反应、金属络合物也被用于还原胺化，极大的促进了还原胺化反应的高选择性及效率。
具体反应类型介绍：催化氢化：1.通常用Pd/C、Raney-Ni和Pt/C催化氢化；2.如果反应底物含不饱和基团如C=C、CN、NO2则受限；3.反应操作简单，清洁、产率高硼氢化钠还原：硼氢化钠容易还原亚胺，也能够还原醛或者酮化合物，在直接还原亚胺时，如果有此类官能团应该保护起来，防止在还原亚胺时被还原；常用溶剂醇类和四氢呋喃。
硼氢化钠与酸性添加剂和脱水剂共同使用：提高中间体亚胺的活性；体系TFA/DCM、TFA/THF、H2SO4/THF；适合低活性胺，如4-硝基苯胺；可以用分子筛、硫酸钠、硫酸镁、氯化钙做脱水剂。
硼氢化钠与钛（IV）添加剂共同使用：TiCl4或Ti(O-Pr-i)4；辅助亚胺；TiCl4在惰性溶剂中使用如苯、THF、DCM；Ti(O-Pr-i)4可以溶于乙醇、异丙醇、甲苯；这些条件对低活性胺有用硼氢化钠与其他添加剂：氯化锌溶于DCM、THF中使用；三甲基氯硅烷氰基硼氢化钠NaB(CN)H3：有醛或酮存在下，弱酸性pH5-7条件下，选择性还原碳氮双键；氰基在水或醇中有一定的水解，常采用甲醇或乙醇作溶剂；亚胺还原的最佳pH5-7，因此通过添加盐酸甲醇溶液调节酸度；分子筛能够吸水从而促进亚胺的生成，也可以采用硫酸钠或者硫酸镁脱水。
还原胺化
如楼上所说,纯化每一步是关键的,不纯化直接往下投反应,虽然做的很快,但是一旦某个环节出了问题,就会很难发现问题出在哪.第一步要纯化一下,哪怕过个柱子,第二步还原胺化反应,建议用1,2-二氯乙烷做溶剂反应体系中加醋酸催化,另加无水MgSO4,或者活化的分子筛.量大的化直接亚胺也行,用甲苯做溶剂,分水器分水,最后反应体系无需后处理,直接加入NaBH(CN)3还原.NaBH(CN)3还原的好处就是只还原亚胺,不还原醛基(书本知识,没有试过,不过听同事也是这么说的,我相信他们做过),这样有利于分离纯化.因为吡啶甲醇的极性不会小,做过有点体会.这步做纯了,下步掉Boc就没有问题了.2.你的问题主要是还原胺化这步，我做一系列的还原胺化，觉得下面的这个条件可以通用：胺一个当量，醛4个当量，加点醋酸，甲醇作溶剂，加三个当量的氰基硼氢化钠，常温反应就可以了。
）这个反应中的亚胺大部分相当不稳定，和原料是平衡的。
生成了，也检测不准。
我们做都不检测2）酸性有利于加快还原速度，但pH要大于53）溶剂，试剂最好无水4）三乙酰氧基硼氢化钠分批加5)最好通氮气隔绝空气和水6）)这个反应用四氢呋喃做溶剂的多，二氯甲烷也可以。
我刚做过一个还原胺化的优化，在甲醇中做的，有少量水存在对收率影响不大，但溶剂中水量增加会对反应有影响，增加到50%就完全得不到产物了。
得到的是一个副产物，因为是氨基酸溶解度不好没做核磁，不知道结构。
但肯定不是原料。
DCM or DCE做溶剂，加入2.0~3.0eq 乙醛+0.1eq 醋酸催化室温搅拌2. 等肼完全转化为亚胺之后，加入NaCNBH3 or Na（OAc)3BH 室温搅拌。
哪怕过个柱子,第二步还原胺化反应,建议用1,2-二氯乙烷做溶剂反应体系中加醋酸催化,另加无水MgSO4,或者活化的分子筛.量大的化直接亚胺也行,用甲苯做溶剂,分水器分水,最后反应体系无需后处理,直接加入NaBH(CN)3还原.NaBH(CN)3还原的好处就是只还原亚胺,不还原醛基(书本知识,没有试过,不过听同事也是这么说的,我相信他们做过),这样有利于分离纯化.因为吡啶甲醇的极性不会小,做过有点体会.这步做纯了,下步掉Boc就没有问题了.有几篇文献可以看看J. Org. Chem. 1996, 61, 3849-3862Org. Lett., 2006, 8, 3307-3310J. Org. Chem., 2005, 70, 2195-2199.Org. Lett., 2006, 8, 741-744.Org. Lett., 2006, 8, 3533-3536.Tetrahedron, 2004, 60, 1463-1471.Tetrahedron, 2004, 60, 7899-7906.Chem. Commun., 2000, 1857-1858.你需要的话和我联系Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination ProceduresJ. Org. Chem. 1996, 61, 3849-3862还原胺化收率低可以有一个办法提高，那就是分两步走，肯定是你的氨碱性太弱，你可以在较高的温度和加入脱水剂先生成亚氨，然后再加入硼氢化钠或者是氰基硼氢化钠，最好是后者，效果非常的好加酸是可以的，但必须是催化量的，氰基硼氢化钠不还原羰基，所以什么时候加都可以，但是硼氢化钠可以还原羰基，要等生成亚胺之后才能加。
还原胺化反应步骤
还原胺化反应是有机化学中的一种常见反应类型，它是指酮或醛与胺在还原剂的存在下发生反应，生成相应的胺化合物。
一种常见的还原胺化反应是通过氢气和催化剂进行的，这个过程一般分为几个步骤：
1.氢气的吸附：
-酮或醛在催化剂的作用下吸附氢气，形成中间体。
常用的催化剂包括铂、钯、镍等。
2.氢气的加成：
-吸附了氢气的酮或醛与氢气发生加成反应。
在此过程中，氢气的氢原子被加到羰基碳上，形成醇中间体。
3.胺的进攻：
-胺分子进攻醇中间体，发生胺化反应。
这一步形成的中间体是胺基醇。
4.脱水：
-胺基醇中间体脱水，生成最终的胺化合物。
这是一个通用的过程，具体反应条件和催化剂可能因反应物的不同而异。
在实际应用中，还原胺化反应常用于合成氨基醇、氨基酮等有机化合物。
还原胺化试剂
还原胺化试剂
以下是一些常见的还原胺化试剂：
1. 硼氢化钠（NaBH4）：是一种常用的还原胺化试剂，它可以在温和的条件下将醛或酮还原为胺。
但是，它对含有官能团的醛或酮反应效果不佳。
2. 氢化铝锂（LiAlH4）：是一种强还原剂，可以在较温和的条件下将醛或酮还原为胺。
但是，它对含有官能团的醛或酮反应效果不佳，并且需要在无水条件下使用。
3. 三叔丁基硼（TBAB）：是一种温和的还原胺化试剂，可以在室温下将醛或酮还原为胺。
但是，它对含有官能团的醛或酮反应效果不佳。
4. 二异丙基氨基锂（LDA）：是一种强还原剂，可以在室温下将醛或酮还原为胺。
但是，它对含有官能团的醛或酮反应效果不佳，并且需要在无水条件下使用。
5. 三乙胺硼氢化锂（LiBH(sec-C4H9)3）：是一种温和的还原胺化试剂，可以在室温下将醛或酮还原为胺。
它对含有官能团的醛或酮反应效果较好，并且不需要在无水条件下使用。
有机化学基础知识点整理胺的氧化与还原反应
有机化学基础知识点整理胺的氧化与还原反应有机化学基础知识点整理——胺的氧化与还原反应胺是一类含有氨基基团的有机化合物，根据氨基基团的数量和位置的不同，可以分为一胺、二胺、三胺等多种类型。
胺化合物在化学反应中具有重要的地位，其中胺的氧化与还原反应是其关键的反应类型之一。
在本文中，我们将对胺的氧化与还原反应进行整理和探讨。
一、胺的氧化反应胺的氧化反应是指胺化合物与氧化剂之间的化学反应过程。
通常情况下，胺的氧化反应可以分为两类：氧化为羧酸和氧化为亚硝基化合物。
1.1 氧化为羧酸一胺和二胺可以通过氧化反应形成相应的羧酸。
常用的氧化剂包括过氧化氢（H2O2）、高锰酸钾（KMnO4）等。
以氨为例，其氧化反应可表示如下：2NH3 + H2O2 → NH2OH + H2ONH2OH + H2O2 → NH2NO2 + 2H2ONH2NO2 + H2O2 → NH2NO3 + H2O由上述反应可见，氨首先被氧化为羟胺，然后再被进一步氧化为亚硝胺和硝胺，最终生成亚硝酸和硝酸。
类似地，亚胺和二胺也可通过类似的反应途径进行氧化反应，生成相应的羧酸。
1.2 氧化为亚硝基化合物胺化合物可以通过氧化反应生成亚硝基化合物。
亚硝基化合物是一类具有亚硝基（-NO）基团的化合物，常见的有亚硝胺和亚硝酰基。
这类反应常见的氧化剂包括亚硝酸钠（NaNO2）、亚硝酸等。
以亚胺为例，其氧化反应可表示如下：R-NH2 + NaNO2 + HCl → R-NO + NaCl + 2H2O类似地，一胺和二胺等胺化合物也可通过类似的反应途径生成亚硝基化合物。
二、胺的还原反应胺的还原反应是指胺化合物与还原剂之间的化学反应过程。
胺的还原反应可分为两类：还原为亚胺和还原为胺。
2.1 还原为亚胺亚硝基化合物如亚硝胺和亚硝酰基可以通过还原反应生成相应的亚胺。
亚硝胺还原反应常用的还原剂有亚硫酸钠（Na2SO3）、氢气等。
以亚硝胺为例，其还原反应可表示如下：R-NO + 2H2SO3 → R-NH2 + 2SO2 + H2O类似地，亚硝酰基也可通过还原反应生成亚胺。
还原胺化 用盐酸盐
还原胺化用盐酸盐
摘要：
一、引言
二、什么是还原胺化
三、盐酸盐在还原胺化中的作用
四、还原胺化的应用
五、结论
正文：
一、引言
在化学领域，还原胺化是一种重要的有机合成反应。
通过这一反应，可以在分子中引入胺基，从而得到具有生物活性的化合物。
近年来，随着科学技术的发展，还原胺化反应已被广泛应用于制药、材料科学等领域。
本文将重点介绍还原胺化反应及其中盐酸盐的作用。
二、什么是还原胺化
还原胺化，顾名思义，是指在还原条件下，将胺转化为胺基化合物的过程。
在这个过程中，一个氢原子被取代，形成一个新的化学键。
还原胺化通常需要催化剂和还原剂，以实现高效、高选择性的反应。
三、盐酸盐在还原胺化中的作用
盐酸盐在还原胺化反应中扮演着重要的角色。
首先，盐酸盐可以作为催化剂，提高反应速率和选择性。
在反应过程中，盐酸盐与胺反应生成亚胺盐酸盐，进而转化为目标胺基化合物。
其次，盐酸盐还可以作为还原剂，提供还原电子，促使反应进行。
通过这一系列过程，盐酸盐实现了在还原胺化反应中的
双重作用。
四、还原胺化的应用
由于还原胺化反应具有广泛的应用前景，因此备受关注。
在制药领域，许多药物分子中都含有胺基，如抗病毒药物、抗肿瘤药物等。
通过还原胺化反应，可以合成这些具有生物活性的化合物，从而用于治疗疾病。
此外，在材料科学领域，还原胺化反应也被用于制备高性能聚合物、液晶等。
五、结论
总之，还原胺化反应在化学领域具有重要意义。
盐酸盐在反应过程中发挥了关键作用，既作为催化剂，又作为还原剂。
还原胺化反应综述
Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride.Studies on Direct and Indirect ReductiveAmination Procedures1Ahmed F.Abdel-Magid,*Kenneth G.Carson,Bruce D.Harris,Cynthia A.Maryanoff,andRekha D.ShahThe R.W.Johnson Pharmaceutical Research Institute,Department of Chemical Development,Spring House,Pennsylvania19477Received January8,1996XSodium triacetoxyborohydride is presented as a general reducing agent for the reductive amination of aldehydes and ketones.Procedures for using this mild and selective reagent have been developed for a wide variety of substrates.The scope of the reaction includes aliphatic acyclic and cyclic ketones,aliphatic and aromatic aldehydes,and primary and secondary amines including a variety of weakly basic and nonbasic amines.Limitations include reactions with aromatic and unsaturated ketones and some sterically hindered ketones and amines.1,2-Dichloroethane(DCE)is the preferred reaction solvent,but reactions can also be carried out in tetrahydrofuran(THF)and occasionally in acetonitrile.Acetic acid may be used as catalyst with ketone reactions,but it is generally not needed with aldehydes.The procedure is carried out effectively in the presence of acid sensitive functional groups such as acetals and ketals;it can also be carried out in the presence of reducible functional groups such as C-C multiple bonds and cyano and nitro groups.Reactions are generally faster in DCE than in THF,and in both solvents,reactions are faster in the presence of AcOH.In comparison with other reductive amination procedures such as NaBH3CN/MeOH,borane-pyridine, and catalytic hydrogenation,NaBH(OAc)3gave consistently higher yields and fewer side products. In the reductive amination of some aldehydes with primary amines where dialkylation is a problem we adopted a stepwise procedure involving imine formation in MeOH followed by reduction with NaBH4.IntroductionThe reactions of aldehydes or ketones with ammonia, primary amines,or secondary amines in the presence of reducing agents to give primary,secondary,or tertiary amines,respectively,known as reductive aminations(of the carbonyl compounds)or reductive alkylations(of the amines)are among the most useful and important tools in the synthesis of different kinds of amines.The reaction involves the initial formation of the intermediate carbinol amine3(Scheme1)which dehydrates to form an imine.Under the reaction conditions,which are usually weakly acidic to neutral,the imine is protonated to form an iminium ion4.2Subsequent reduction of this iminium ion produces the alkylated amine product5. However,there are some reports that provide evidence suggesting a direct reduction of the carbinol amine3as a possible pathway leading to5.3The choice of the reducing agent is very critical to the success of the reaction,since the reducing agent must reduce imines (or iminium ions)selectively over aldehydes or ketones under the reaction conditions.The reductive amination reaction is described as a direct reaction when the carbonyl compound and the amine are mixed with the proper reducing agent without prior formation of the intermediate imine or iminium salt.A stepwise or indirect reaction involves the prefor-mation of the intermediate imine followed by reduction in a separate step.The two most commonly used direct reductive amina-tion methods differ in the nature of the reducing agent. The first method is catalytic hydrogenation with plati-num,palladium,or nickel catalysts.2a,4This is an economical and effective reductive amination method, particularly in large scale reactions.However,the reac-tion may give a mixture of products and low yields depending on the molar ratio and the structure of the reactants.5Hydrogenation has limited use with com-pounds containing carbon-carbon multiple bonds and in the presence of reducible functional groups such as nitro6,7and cyano7groups.The catalyst may be inhibited by compounds containing divalent sulfur.8The second method utilizes hydride reducing agents particularly sodium cyanoborohydride(NaBH3CN)for reduction.9The successful use of sodium cyanoborohydride is due to its stability in relatively strong acid solutions(∼pH3),its solubility in hydroxylic solvents such as methanol,and its different selectivities at different pH values.10At pHX Abstract published in Advance ACS Abstracts,May1,1996.(1)Presented in part at the33rd ACS National Organic Symposium, Bozeman,Mo,June1993,Paper A-4.Preliminary communications:(a) Abdel-Magid,A.F.;Maryanoff,C.A.;Carson,K.G.Tetrahedron Lett. 1990,31,5595.(b)Abdel-Magid,A.F.;Maryanoff,C.A.Synlett1990, 537.(2)The formation of imines or iminium ions was reported as possible intermediates in reductive amination reactions in catalytic hydrogena-tion methods,see(a)Emerson,.React.1948,4,174and references therein.It was also proposed in hydride methods,see(b) Schellenberg,.Chem.1963,28,3259.(3)Tadanier,J.;Hallas,R.;Martin,J.R.;Stanaszek,R.S.Tetra-hedron1981,37,1309(4)(a)Emerson,W.S.;Uraneck,C.A.J.Am.Chem.Soc.1941,63, 749.(b)Johnson,H.E.;Crosby,.Chem.1962,27,2205.(c)Klyuev,M.V.;Khidekel,M.L.Russ.Chem.Rev.1980,49,14.(5)Skita,A.;Keil,F.Chem.Ber.1928,61B,1452.(6)Roe,A.;Montgomery,J.A.J.Am.Chem.Soc.1953,75,910.(7)Rylander,P.N.In Catalytic Hydrogenation over Platinum Metals;Academic Press,New York,1967;p128.(8)Rylander,P.N.In Catalytic Hydrogenation over Platinum Metals;Academic Press,New York,1967;p21.(9)For a recent review on reduction of C d N compounds with hydride reagents see:Hutchins,R.O.,Hutchins,M.K.Reduction of C d N to CHNH by Metal Hydrides.In Comprehensive Organic Synthesis;Trost, B.N.,Fleming,I.,Eds.;Pergamon Press:New York,1991;Vol.8.3849.Chem.1996,61,3849-3862S0022-3263(96)00057-6CCC:$12.00©1996American Chemical Society3-4it reduces aldehydes and ketones effectively,but this reduction becomes very slow at higher pH values.11At pH6-8,the more basic imines are protonated preferen-tially and reduced faster than aldehydes or ketones.10 This selectivity allows for a convenient direct reductive amination procedure.The literature is replete with publications that document the use of sodium cyanoboro-hydride in reductive amination reactions.12Limitations are that the reaction may require up to a fivefold excess of the amine,10is usually slow and sluggish with aromatic ketones10and with weakly basic amines,13and may result in the contamination of the product with cyanide.14The reagent is highly toxic15and produces toxic byproducts such as HCN and NaCN upon workup.Other reported reductive amination reagents include borane-pyridine,13a Ti(OiPr)4/NaBH3CN,13b borohydride exchange resin,16a Zn/AcOH,16b NaBH4/Mg(ClO4)2,16c and Zn(BH4)2/ZnCl2.16d In addition,there are some reports of electrochemical reductive amination reactions.17In our work on hydride-induced reductive aminations of aldehydes and ketones,we sought an alternative to the toxic sodium cyanoborohydride to eliminate the risk of residual cyanide in the product and in the workup waste stream,particularly for large scale reactions.Af-ter surveying many of the commercially available hy-dride reagents,we selected sodium triacetoxyborohydride [NaBH(OAc)3].18This borohydride reagent is mild and exhibits remarkable selectivity as a reducing agent.It reduces aldehydes selectively over ketones,18except for -hydroxy ketones which can be reduced selectively to give1,3-trans diols.19The steric and the electron-withdrawing effects of the three acetoxy groups stabilize the boron-hydrogen bond and are responsible for its mild reducing properties.20Our selection was also based on the results of reductive alkylation of amines using sodium borohydride in neat liquid carboxylic acids reported earlier by Gribble et al.21In this paper we report the results of our comprehen-sive investigation of the scope and limitations of sodium triacetoxyborohydride in a procedure for direct reductive amination of aldehydes and ketones with a variety of aliphatic and aromatic amines.This report also includes an alternative stepwise route for the reductive amination of aldehydes with primary amines which involves the preformation of imines and their subsequent reduction with NaBH4in one-pot reactions.Results and DiscussionsThe direct reductive amination reactions were carried out in1,2-dichloroethane(DCE),tetrahydrofuran(THF), or acetonitrile.The standard reaction conditions are as follows:a mixture of the carbonyl compound and the amine(0-5%molar excess)in the desired solvent is stirred with1.3-1.6equiv of sodium triacetoxyborohy-dride under a nitrogen atmosphere at room temperature. In some reactions,acetic acid(1-2mol equiv)is added to the mixture.The progress of the reaction is followed by GC and GC/MS analysis.The results from various reductive amination reactions of ketones and aldehydes are listed in Tables1and2,respectively.Solvents such as water or methanol are not recommended.Reactions in methanol resulted in a fast reduction of the carbonyl compound,and the reagent decomposed in water. (a)Reductive Amination of Ketones.The results in Table1show that the reductive amination of a wide variety of cyclic and acyclic ketones with primary and(10)Borch,R.F.;Bernstein,M.D.;Durst,H.D.J.Am.Chem.Soc. 1971,93,2897.(11)Borch,R.F.,Durst,H.D.J.Am.Chem.Soc.1969,91,3996.(12)(a)Hutchins,R.O.;Natale,.Prep.Proced.Int.1979, 11(5),201.(b)Lane,C.F.Synthesis1975,135.(13)Occasional use of weakly basic or nonbasic amines was reported, see for example:(a)Pelter,A.,Rosser,R.M.,Mills,S.J.Chem.Soc., Perkin Trans.11984,717.(b)Mattson,R.J.,Pham,K.M.;Leuck,D. J.;Cowen,.Chem.1990,55,2552.(c)Borch,R.F.;Hassid, .Chem.1972,37,1673.(d)Marchini,P.;Liso,G.;Reho,A.; Liberatore,F.;Moracci,.Chem.1975,40,3453.(14)(a)The product from large scale reduction of the imine(i)with sodium cyanoborohydride was contaminated with cyanide.(b)A similar result was reported recently:Moormann,mun.1993, 23,789.(15)For information on the safety data and health hazards associ-ated with sodium cyanoborohydride see:The Sigma-Aldrich Library of Chemical Safety Data,1st ed.;Lenga,R.E.,Ed.,Sigma-Aldrich Corp.:Milwaukee,1985,p1609.(16)(a)Yoon,N.M.;Kim,E.G.;Son,H.S.;Choi,mun. 1993,23,1595.(b)Micovic,I.V.;Ivanovic,M.D.;Piatak,D.M.;Bojic, V.Dj.Synthesis1991,1043.(c)Brussee,J.;van Benthem,R.A.T.M.; Kruse,C.G.;van der Gen,A.Tetrahedron:Asymmetry1990,1,163.(d)Bhattacharyya,S.;Chatterjee,A.;Duttachowdhhury,S.K.J.Chem. Soc.,Perkin Trans.11994,1.(17)(a)Pienemann,T.;Schafer,H.-J.Synthesis1987,1005.(b) Smirnov,Yu.D.;Tomilov,.Chem.U.S.S.R.1992,28(1), 42.(c)Smirnov,Yu.D.;Pavlichenko,V.F.;Tomilov,.Chem. U.S.S.R.1992,28(3),374.(18)(a)Gribble,G.W.;Ferguson, D. C.J.Chem.Soc.,Chem.Commun.1975,535.(b)Nutaitis,C.F.;Gribble,G.W.TetrahedronLett.1983,24,4287.(c)Gribble,G.W.In Encyclopedia of Reagentsfor Organic Synthesis;Paquette,L.A.,Ed.,John Wiley and Sons:NewYork,1995;Vol.7,p4649.(19)See for example:(a)Saksena,A.K.;Mangiaracina,P.Tetra-hedron Lett.1983,24,273.(b)Evans, D. A.;Chapman,K.T.Tetrahedron Lett.1986,27,5939.(c)Evans,D.A.,Chapman,K.T.;Carreira,E.M.J.Am.Chem.Soc.1988,110,3560.(20)Gribble,G.W.;Nutaitis,.Prep.Proced.Int.1985,17,317.(21)Earlier work by Gribble et al.demonstrated the potential oftriacyloxyborohydrides generated from NaBH4in neat liquid carboxylic acids in reductive alkylation of amines:(a)Gribble,G.W.;Lord,P.D.;Skotnicki,J.;Dietz,S.E.;Eaton,J.T.;Johnson,J.L.J.Am.Chem.Soc.1974,96,7812.(b)Gribble,G.W.;Jasinski,J.M.;Pellicone,J.T.;Panetta,J.A.Synthesis1978,766.Scheme1.Chem.,Vol.61,No.11,1996Abdel-Magid et al.secondary amines was successful under the standard conditions and gave the desired products in good to excellent yields.The scope of the reaction includes different alicyclic ketones,from cyclobutanone to cy-clododecanone(Table1:entries1-23),bicyclic ketones such as norcamphor and tropinone(Table1:entries24-30),saturated acyclic ketones(Table1:entries31-39), and keto esters(Table1:entries47-49).Nearly all primary and nonhindered secondary amines were used successfully in these reactions.For the same ketone,the rate of the reaction was dependent on the steric and electronic factors associated with the amines.In general, primary aliphatic amines reacted faster than primary aromatic and secondary aliphatic amines(Table1:en-tries10vs11;14and15vs16and17;24vs26and27). Cyclic secondary amines such as morpholine reacted faster than acyclic secondary amines such as diethyl-amine(Table1:entry33vs36)while the sterically hindered diisopropylamine did not react even after days (Table1:entry45).In some slow reactions(e.g.,Table 1:entries11,27,32,34,and36),small amounts of side products were formed(1-5%by GC area%analysis) from N-ethylation and N-acetylation of the starting amines.22These impurities were easily removed in the workup or during the recrystallization of the salts. The reaction conditions are very mild and can tolerate the presence of acid sensitive functional groups such as acetals and ketals.For example,the reductive amination of cyclohexanedione monoethylene ketal with primary and secondary amines afforded good to excellent isolated yields of the corresponding amines(Table1:entries14-18).Another example is the reductive alkylation of aminoacetaldehyde diethyl acetal with cyclododecanone (Table1:entry9).A particularly useful example is the reaction involving cyclohexanedione monoethylene ketal and aminoacetaldehyde diethyl acetal(Table1:entry18) which provides a secondary amine product containing protected aldehyde and ketone functionalities in a nearly quantitative yield.Of all the ketones used in this study,small aliphatic cyclic ketones,ranging from cyclobutanone to cyclohex-anone,were most rger cyclic ketones such as cyclooctanone and cyclododecanone and acyclic ketones such as2-heptanone reacted somewhat slower.Reactiv-ity of cyclobutanone was so high that its reaction with benzylamine gave a mixture of mono-and dicyclobutyl-benzylamines even with the use of excess amine(Table 1:entry2).Clean formation of N,N-dicyclobutylbenzyl-amine resulted with the use of a1:2molar ratio of amine to ketone(Table1:entry1).The reactions with second-ary amines were very effective since there was no dialkylation product(Table1:entry3).The least reactive ketones were aromatic,R, -unsatur-ated,and sterically hindered ketones.Aromatic and R, -unsaturated ketones reacted very slowly(Table1:entries 40,41,and43).Experimentally,a saturated aliphatic ketone was reductively aminated,selectively,and quan-titatively in the presence of an aromatic or R, -unsatur-ated ketone(Table1:entries42and44).The unreacted ketones were recovered unchanged except for the forma-tion of trace amounts of their imines(as determined by GC/MS analysis of the reaction mixture).Sterically hindered ketones were even less reactive than aromatic and R, -unsaturated ketones,e.g.,camphor showed no reaction with benzylamine after four days(Table1:entry 46).The steric factors associated with both ketones and amines seem to be very important in determining the outcome of the reaction.In reactions where the formation of diastereomers was possible,we observed varying degrees of selectivity. Reductive amination of4-tert-butylcyclohexanone with pyrrolidine and cyclohexylamine occurred with a moder-ate diastereoselectivity to give the thermodynamically less favored cis products.This results from equatorial attack by the hydride reagent on the intermediate imine, to form the axial amine(Table1:entries19and20).23 The reductive amination of androstanolone with isopro-pylamine gave a mixture of3R-and3 -(isopropylamino)-androstan-17 -ol in about25:75ratio(Table1:entry21). The reactions involving bicyclic ketones showed higher degrees of diastereoselectivity.For example,the reduc-tive aminations of norcamphor led to the exclusive formation of the endo products,from exo attack by the hydride reagent.The reductive amination of norcamphor with benzylamine(Table1:entry24)produced a single product.This product was identical to that obtained from the reductive amination of benzaldehyde with endo-2-aminonorbornane(Table2:entry13),thus confirming the endo stereochemistry of the product.Reductive amination of tropinone with primary amines such as benzylamine and aniline(Table1:entries28and 29)was accomplished in good yield and high diastereo-selectivity giving the endo isomer as the major product (determined by1H NMR).24The reaction with benzyl-amine gave the endo and exo products in approximately 20:1ratio while the reaction with aniline showed no detectable exo product.The reaction of tropinone with piperidine was extremely sluggish giving low conversion to about a1:1mixture of the exo-and endo-products after four days of reaction(Table1:entry30).The poor solubility of ammonium acetate in DCE,THF, or CH3CN limits its use in the reductive amination of ketones to prepare primary amines.The initial primary amine product is much more soluble than ammonium acetate and reacts faster with the ketone to generate dialkylamines,so this reaction can be used for the preparation of symmetrical dialkylamines.The amina-tion reaction is relatively slow and some ketone reduction may occur if AcOH is added.Even the use of a large excess(10equiv)of ammonium acetate in THF,DCE,or CH3CN,in the presence of Et3N,did not favor the formation of the monoalkylamine,the only product formed was dicycloheptylamine(Table1:entries22 and23).N-Substituted R-amino esters were prepared by the reductive amination of R-keto esters with primary and(22)The N-ethylation of amines is a major process in reaction of amines with sodium borohydride in neat acetic acid and is believed to proceed through an acetaldehyde formation.21a(23)This result is consistent with literature reports on the reduction of4-substituted cyclohexanone imines or iminium salts which con-cluded that bulky hydride reagents such as L-Selectride attack preferentially from the less hindered equatorial side to give the cis-products,while less bulky hydride reagents such as NaBH4and NaBH3-CN slightly favor the axial approach,see:(a)Wrobel,J.E.;Ganem, B.Tetrahedron Lett.1981,22,3447.(b)Hutchins,R.O.;Markowitz, .Chem.1981,46,3571.(c)Hutchins,R.O.;Su,W.-Y.; Sivakumar,R.;Cistone,F.;Stercho,.Chem.1983,48,3412.(d)Hutchins,R.O.;Adams,J.;Rutledge,.Chem.1995, 60,7396.(24)Chemical shift assignments of individual protons were arrived at by COSY,HETCOR,and Inverse HMBC NMR experiments.The stereochemistry of N-phenyl-3-aminotropane and N-benzyl-3-aminotro-pane was assigned based on1D NOE and coupling experiments.The assignments were in line with other literature reports;cf.Bagley,J. R.;Riley,T.N.J.Hetrocycl.Chem.1977,14,599and references therein.Reductive Amination of Aldehydes and Ketones .Chem.,Vol.61,No.11,19963851Table 1.Reductive Amination ofKetones.Chem.,Vol.61,No.11,1996Abdel-Magid et al.secondary amines.The reductive amination of methyl pyruvate with benzylamine was a fast and efficient reaction under the standard conditions that gave N -benzylalanine methyl ester in an excellent yield (Table 1:entry 47).The reaction was slower with hindered keto esters such as methyl 3-methyl-2-oxobutanoate (Table 1:entry 48),and the competing ketone reduction was a major reaction.The aromatic keto ester,methyl benzoyl formate reacted even slower with benzylamine and was also accompanied by considerable ketone reduction (Table 1:entry 49).Reactions involving other less reactive amines such as aniline or morpholine were much slowerTable 1.(Continued)Reductive Amination of Aldehydes and Ketones.Chem.,Vol.61,No.11,19963853and gave increasing amounts of ketone reductions. Whenever ketone reduction was a problem,the conditions were modified to use the amines as limiting reagents. The excess ketones were completely reduced to the corresponding alcohols which required the occasional addition of excess reducing agent.N-Substituted R-ami-no esters were also prepared by the reductive amination of R-amino esters with ketones,e.g.,N-(2-butyl)glycine ethyl ester was prepared in very good yield from ethyl glycinate and2-butanone(Table1:entry50).The reductive amination of cyclohexanedione mono-ethylene ketal with phenylhydrazine gave cleanly the N-substituted phenylhydrazine(Table1:entry51)in nearly quantitative yield.Other ketones such as cyclo-hexanone and2-heptanone reacted to give similar prod-ucts(Table1:entries52and53);however,there were some competing side reactions.The crude products showed the formation of byproducts,about15%with cyclohexanone and31%with2-heptanone.Attempted reductive amination of cyclooctanone with hydroxylamine was not successful and resulted in the oxime formation (Table1:entry54).Reductive aminations in which diamines containing both primary and secondary amino groups were studied and in general,primary amines reacted faster.In the case where the primary amino group was aliphatic and the secondary group was aromatic,e.g.,N-phenylethyl-enediamine,there was a clear difference in reactivity between the two amines.The reaction with4-heptanone gave a quantitative yield of the product resulting from exclusive reaction with the primary amine(Table1: entry55).In the case where both amino groups were aliphatic,such as1-(2-aminoethyl)piperazine,there was a high selectivity(94:6)for the primary group in reaction with acetylcyclohexane(Table1:entry56).(b)Reductive Amination of Aldehydes.Unlike ketones,aldehydes can be reduced with sodium triac-etoxyborohydride.18Thus,the possibility exists that the reduction of the aldehyde would compete with the reduc-tive amination process under the standard conditions. However,these conditions were so selective that the reductive aminations with aldehydes occurred very ef-fectively and resulted in fast reactions with no aldehyde reductions in most cases studied(Table2).One case in which aldehyde reduction was detected involved a reac-tion with the very sterically hindered diisopropylamine (Table2:entry6).All other examples in Table2resulted in fast and efficient reductive aminations with a variety of aliphatic primary and secondary amines as well as aniline with no detectable aldehyde reductions.Both aliphatic and aromatic aldehydes were very reactive and gave reductive amination products with a broad variety of primary and secondary amines.The reaction times ranged from20min to24h.The mildness of the reac-tion conditions is well illustrated in the reductive ami-nation of1,1′,2-tris-nor-squalene aldehyde with dieth-ylamine and diisopropylamine(Table2:entries19and 20).The aldehyde was cleanly converted to the corre-sponding amines in high yields with no detectable side reactions.In the reductive amination of aldehydes with primary amines,formation of dialkylated amines is a common side reaction.5This side reaction was rarely a problem in most reactions reported in Table2.In the few cases when it was detected,it was suppressed by the addition of up to5%molar excess of the primary amine.However, the dialkylation of amines remained a problem with certain substrates.25An alternative stepwise procedure for such systems is discussed later in this paper. Some aldehydes,such as formaldehyde and glutaral-dehyde are only available commercially as aqueous solutions which may restrict their use under the above reaction conditions because of the decomposition of the hydride reagent with water.However,the reaction may be carried out in DCE with excess hydride reagent,e.g., the reductive amination of either aqueous glutaraldehyde or formaldehyde with1-phenylpiperazine and about4 hydride equivalents was carried out on10mmol scale (Table2:entries21and22)and gave nearly quantitative yields of the corresponding amines.This,however,may not be suitable for large scale reactions.The use of phenylhydrazine in reductive amination of benzaldehyde was not successful,resulting only in hy-drazone formation.Generally,with either ketones or aldehydes,reactions in DCE were noticeably faster than those carried out in THF(e.g.,Table1:entries6vs7;25vs26and Table2: entries3vs4;9vs10).Also,in the same solvent, reactions were consistently faster in the presence of1 (or more)mol equiv of acetic acid.For most ketones, reactions were improved in the presence of acetic acid. However,the addition of acetic acid is not always advantageous to the reaction.Most reactions with al-dehydes are fast and do not require addition of AcOH. Addition of AcOH to a slow reaction,e.g.,cyclohexan-ecarboxaldehyde with diisopropylamine,resulted in a fast reaction accompanied with about25%aldehyde reduc-tion,and the yield of the isolated desired product was only41%.When the reaction was carried out in the absence of AcOH,the reaction was slower;however,the aldehyde reduction was only about5%,and the isolated yield of the purified reductive amination product in-creased to75%(Table2:entries6and7).Direct com-parisons were made between reactions in DCE and THF and with or without added acetic acid in representative reactions.The rate of product formation was determined quantitatively26in each case.The results of these com-parisons were in agreement with the above observations.(c)Reductive Amination with Weakly Basic and Nonbasic Amines.Few literature references have dealt with aromatic amines containing electron withdrawing substituents in reductive amination reactions.13,21a Cata-lytic hydrogenation conditions do not allow the presence of many of the easily reduced electron-withdrawing substituents such as cyano and nitro groups,since these substituents are often reduced under catalytic hydroge-nation conditions.6,7On the other hand,we and others13a,b have found the most used hydride reagent,sodium cyanoborohydride[NaBH3CN],to be sluggish and inef-ficient when used with these weak bases in reductive amination reactions.As a consequence of substitution by electron-withdraw-ing substituents,these amines are both poor nucleophiles and weak bases(e.g.,p K a3.98for4-chloroaniline,1.02 for4-nitroaniline,-0.29for2-nitroaniline,-4.26for2,4-dinitroaniline).27This slows the initial nucleophilic at-(25)For a discussion of the dialkylation side reactions involvingγ-andδ-amino esters with aldehydes and a mechanistic explanation, see:Abdel-Magid,A.F.;Harris,B.D.;Maryanoff,C.A.Synlett1994, 81.(26)The progress of these reactions was followed by GC.Linear standard curves of the response factors by GC areas of starting materials and expected products were determined to allow the quantitative measurements of their concentrations in the reaction mixtures..Chem.,Vol.61,No.11,1996Abdel-Magid et al.tack on the carbonyl carbon and leads to slower overall reaction rates (Scheme 2).In addition,the carbonyl group now competes effectively with the less basic intermediate imine for protonation and subsequently for the hydride in the reduction step.2b This may lead to a significant carbonyl reduction,consumption of both the carbonyl compound and the reducing agent and low yields of the reductive amination products.The reducing agent and reaction conditions should be chosen carefully to minimize such side reactions.Table 2.Reductive Amination ofAldehydesReductive Amination of Aldehydes and Ketones .Chem.,Vol.61,No.11,19963855Sodium triacetoxyborohydride is very efficient in re-ductive amination reactions with such unreactive amines. The results from several reactions are listed in Table3. In several cases such as monosubstituted anilines(e.g., p-nitro-p-carbethoxy-,and p-cyanoanilines),the standard reaction conditions described previously(about1:1ratio of carbonyl compound to amine,1.4equiv of NaBH(OAc)3 with1equiv of acetic acid)were adequate.However, with less basic amines such as o-nitroaniline,2,4-dichlo-roaniline,or2-aminothiazole,the reaction conditions were modified to compensate for the aforementioned effects and to maximize the yields of the reductive amination products.The optimum conditions included the use of the amine as the limiting reagent with1.5-2 mol equiv of the carbonyl compound,2-3equiv of NaBH-(OAc)3,and2-5equiv of AcOH in1,2-dichloroethane. Under these conditions,a variety of weakly basic amines were successfully employed in the reductive aminations of ketones and aldehydes in isolated yields ranging from 60%to96%.The reaction is convenient and the condi-tions are mild and show a high degree of tolerance for a variety of functional groups including nitro,cyano,halo, carboxy,and carbethoxy groups.Ketones reacted effectively with p-monosubstituted anilines to give good yields of the reductive amination products(Table3:entries1-8).The reaction was slightly slower with2,4-dichloroaniline and gave a high yield of the desired reductive amination product in addition to some ketone reduction and the formation of about3%of N-ethyl-2,4-dichloroaniline(Table3:entry 9).The reaction became very slow with o-nitroaniline which progressed only to about30%conversion to the reductive amination product and17%of N-ethyl-2-nitroaniline after6days(Table3:entry10).The reaction stopped completely when both ortho positions were substituted as in2,6-dibromo-and2,4,6-trichloro-anilines(Table3:entries11and12).The reactions with aldehydes were faster than those with ketones and gave higher yields from similar reac-tions.Aldehyde reductions occurred only with the least reactive amines.In the reductive amination of aldehydes with p-carboxyaniline and p-nitroaniline(Table3:en-tries13,14,and18),no competing aldehyde reduction was observed.In these cases,the standard conditions were used.With weaker amines such as2,4-dichloro-aniline and o-nitroaniline(Table3:entries15and16), the conditions were modified to use the amine as a limiting reagent since aldehyde reduction occurred to the extent of10-30%.This procedure was applied to other weakly basic primary amines such as2-aminothia-zole(Table3:entries22and23)and secondary amines such as iminostilbene(Table3:entry24).While imi-nostilbene reacted with hexanal to give a high yield of the N-hexyl product,the dihydro analogue iminodiben-zyl gave no reaction under the same conditions(Table3: entry25).One of the most unique reactions,however,was the reductive alkylation of p-toluenesulfonamide with ben-zaldehyde to give the N-benzyl derivative(Table3:entry 26).The reaction is carried out initially under the standard conditions in the presence of Et3N(2equiv). The aldehyde is usually consumed in about24h to give a mixture of N-benzyl p-toluenesulfonamide and N-benzal p-toluenesulfonamide.The reaction mixture is then treated with AcOH(2.5equiv)and additional NaBH(OAc)3(1equiv)to finish the reduction.The reaction,however,was not successful with ketones or carboxamides.The least reactive amines,2,4-dinitroaniline and2,4,6-trichloroaniline failed to undergo reductive amination with benzaldehyde(Table3:entries20and21).Cyclo-hexanecarboxaldehyde,on the other hand,reacted slowly with these two amines to give the corresponding reduc-tive amination products.In these two reactions,the aldehyde reduction became a major reaction process.To assure the presence of enough aldehyde to react with the amine,the reaction required occasional additions of aldehyde and reducing agent,up to5equiv each and over a two to four day period(Scheme3).The reactions progressed to reach90-92%conversion(as determined by GC)and gave61%and58%isolated yields,respec-tively,after chromatography.It is possible that these reactions proceed via initial formation of intermediate enamines rather than imines which may explain the lack of reactivity of aromatic aldehydes which cannot form enamines.(d)Comparison with Other Reducing Agents.In general,the results of reductive amination employing sodium triacetoxyborohydride were as good as or better than most comparable reported results whether done using hydrogenation or hydride reagents.However,in many cases,our results were far superior to others.For example,we compared the reductive amination of cyclo-hexanone with morpholine using NaBH3CN vs NaBH-(OAc)3.The reaction with NaBH3CN(6hydride equiv) in methanol and in the absence of AcOH was only34% complete after23h with the formation of about10%of the corresponding enamine.The conversion improved to 50%in23h with AcOH(1equiv)with no enamine formation.The reaction using the standard NaBH(OAc)3 conditions was99.8%complete in3h without a trace of enamine formation(Table1:entry5).In another comparison,the reductive amination of1-carbethoxy-4-piperidinone with p-chloroaniline was only45%complete with NaBH3CN after22h but was>96%with NaBH-(OAc)3in2.5h(Table3:entry4).An impressive result was obtained in the reductive amination of1,1′,2-tris-nor-squalene aldehyde with di-ethylamine and isopropylamine.These reactions were reported to give about5%yield under regular Borch conditions.28The yields were improved to46and42%, respectively,when the reactions were carried out with NaBH3CN in anhydrous THF in the presence of HCl(pH 3).29Under our standard conditions,these reactions gave(27)(a)Albert,A.;Serjeant,E.P.In The Determination of Ionization Constants;Chapman and Hall:London,1971;p91.(b)Yates,K;Wai, H.J.Am.Chem.Soc.1964,86,5408.(28)Duriatti,A.;Bouvier-Nave,P.;Benveniste,P.;Schuber,F.; Delprino,L.;Balliano,G.;Cattel,L.Biochem.Pharmacol.1985,34, 2765.(29)Ceruti,M.;Balliano,G.;Viola,F.;Cattel;L.;Gerst,N.;Schuber,F.Eur.J.Med.Chem.1987,22,199.Scheme2.Chem.,Vol.61,No.11,1996Abdel-Magid et al.。
水合肼 还原胺化
水合肼还原胺化
水合肼是一种常用的还原剂，具有极强的还原能力。
在化学反应中，水合肼主要用于羰基化合物的还原。
例如，羰基化合物与等摩尔量的水合肼在正丁醇中回流反应，可以制备腙。
此外，利用水合肼进行还原胺化的反应也是研究的重点。
一种方法是在氢氧化钠或氢氧化钾作用下，使羰基化合物直接与水合肼发生还原反应，从而被广泛用于各种酸敏底物的还原。
在此过程中，羰基化合物的其他不饱和基团（例如：双键等）不受影响。
另一种方法是通过Pd/C或Raney Ni催化加氢还原硝基的方式，将硝基还原为胺，这也是合成胺的最干净和简便的还原方法。
然而，这种方法的缺点是条件比较强，卤素和双键，炔键可能会被还原。
还原胺化最全知识
还原胺化最全知识
胺化是一种重要的生物学反应，它涉及细胞中特定的氨基酸的化学改变。
它发生在氨
基酸被氨基噻吩进行支链氧化反应（transamination）时，氨基酸的偶联位置上消失，从
而产生由胺基组成的硫醇和水溶性产物。
这种形式的反应不仅发生在脂肪酸代谢中，也发
生在蛋白质代谢中。
胺化反应在分子生物学和生物化学中被认为是一种重要的生物学反应，因为它可以从一种氨基酸转换到另一种氨基酸。
此外，在胺化反应中，细胞也会逆转氨基酸，这里也称作逆胺化（deamination）。
逆胺化包括在氨基酸的某个偶联位置上的水分子的添加而产生氨基磷酸（aminephosphate）。
逆胺化反应是生物氨基酸被氨基噻吩进行去氧化反应（transamination）时所发生的一个重要化学反应。
胺化反应不仅仅发生在生物体中，在医学上也可以用于检测不适症状，因为它和人体
免疫系统有关系，可以通过监测血清氨基转移酶（aminotransferase）的活性来检测。
近
年来，胺化技术也被广泛用于新药研发，它可以帮助科学家快速了解药物的作用机制，在
这个过程中，ラット体内的氨基酸及其衍生的分子相互作用及其中间体被评估，这有助于
优化特定药物剂量和安全性。
最后，由于某些氨基酸是不具备活性的，因此，在实验研究中经常使用被称为“小核
胺化”（minor reaction of amination）的一种方法。
该方法可用于制备多种不同类型
的以氨基酸为活性组分的化合物，从而为实验室提供了有用的相互作用物质。
小核胺化是
一种非常有用的合成技术，更重要的是，它可以使这类氨基酸衍生物在体内获得有效的活性。
三仲丁基硼氢化锂 还原胺化
三仲丁基硼氢化锂还原胺化三仲丁基硼氢化锂还原胺化是一种重要的有机合成方法，可以有效地将胺化合物转化为胺化物。
在有机合成领域中，胺化反应是一种常用的方法，可以制备各种各样的胺类化合物，具有广泛的应用价值。
而三仲丁基硼氢化锂还原胺化作为一种高效的还原剂，已经被广泛应用于有机合成领域。
三仲丁基硼氢化锂是一种强还原剂，具有高度的还原性能，可以有效地将含氮化合物中的N-H键还原为N-H键。
胺是一种含有氮原子的有机化合物，通常具有N-H键，与三仲丁基硼氢化锂反应可以发生胺化反应，生成胺化物。
胺化反应是一种重要的有机合成方法，可以制备各种不同类型的胺类化合物，具有广泛的应用前景。
胺类化合物在生物学、药物化学、材料科学等领域具有重要的应用价值。
因此，发展高效、环保的合成方法，是当前研究的热点之一。
三仲丁基硼氢化锂还原胺化作为一种高效的胺化方法，具有许多优点，如反应条件温和、产率高、底物范围广等，受到了广泛关注。
三仲丁基硼氢化锂还原胺化的反应机理相对复杂，主要包括胺化剂与三仲丁基硼氢化锂的反应、氢化过程以及产物的生成等步骤。
在反应过程中，三仲丁基硼氢化锂首先与胺化剂发生反应，生成中间体。
随后，中间体经过氢化反应，将N-H键还原为N-H键，最终生成胺化物。
反应条件、底物结构等因素都会影响三仲丁基硼氢化锂还原胺化的反应效率和选择性。
研究表明，三仲丁基硼氢化锂还原胺化在不同底物上具有不同的反应活性和选择性。
例如，对于一些含有特殊基团的胺化合物，三仲丁基硼氢化锂可能会出现不同程度的副反应。
因此，在设计合成路线时，需要综合考虑底物结构、反应条件以及目标产物的要求，以提高反应的效率和选择性。
在实际应用中，三仲丁基硼氢化锂还原胺化已经被成功应用于一些重要的有机合成反应中。
例如，通过三仲丁基硼氢化锂还原胺化可以高效合成一些医药中间体、农药原料等化合物。
与传统的还原方法相比，三仲丁基硼氢化锂还原胺化具有更高的产率和更好的底物适用性，为有机合成化学提供了新的思路和方法。
还原胺化知识
还原胺化反应，又称鲍奇还原（Borch ห้องสมุดไป่ตู้eduction，区别于伯奇Birch还原反应），是一种简便的把醛酮转换成胺的方法。
机理
首先是胺与羰基加成，缩合，生成羰基的结构类似物西弗碱（Schiff Base），后者接受氢供体的氢传递生成最终产物胺。见图：
方法
将羰基跟胺反应生成亚胺（西弗碱），然后用硼氢化钠或者氰基硼氢化钠还原成胺。反应应在弱酸条件下进行，因为弱酸条件一方面使羰基质子化增强了亲电性促进了反应，另一方面也避免了胺过度质子化造成亲核性下降的发生。用氰代硼氢化钠比硼氢化钠要好，因为氰基的吸电诱导效应削弱了硼氢键的活性，使得氰代硼氢化钠只能选择性地还原西弗碱而不会还原醛、酮的羰基，从而避免了副反应的发生。
改进
用NaBH(OAc)3作还原剂，用ClCH2CH2Cl做溶剂可以缩短反应时间并显着提高产率。
生物体内的反应
生物体内存在类似的过程，是由维生素B6（吡哆醛/胺）和NADPH（大自然的硼氢化钠）来介导的，氨基酸经此可以和酮体（Ketone bodies）相互转换。
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还原胺化反应
还原胺化反应，又称鲍奇还原（Borch reduction,区别于伯奇Birch 还原反应）,是一种 简便的把醛酮转换成胺的方法。
机理
首先是胺与羰基加成，缩合，生成羰基的结构类似物
西弗碱（Schiff Base ，后者接受
氢供体的氢传递生成最终产物胺。
见图： 方法
将羰基跟胺反应生成亚胺（西弗碱），然后用 硼氢化钠或者氰基硼氢化钠还原成胺。
反应 应在弱酸条件下进行，因为弱酸条件一方面使羰基质子化增强了 亲电性促进了反应，另一 方面也避免了胺过度质子化造成亲核性下降的发生。
用氰代硼氢化钠比硼氢化钠要好，因 为氰基的吸电诱导效应削弱了硼氢键的活性，使得氰代硼氢化钠只能选择性地还原西弗碱 而不会还原醛、酮的羰基，从而避免了副反应的发生。
用NaBH （0Ac ）3作还原剂，用CICH 2CH 2CI 做溶剂可以缩短反应时间并显着提高产率。
生物体内的反应
生物体内存在类似的过程，是由 维生素B6（吡哆醛/胺）和NADPH （大自然的硼氢化
钠）来介导的，氨基酸经此可以和 酮体（Ketone bodies
相互转换
2QPO 磷醸毗哆醛
(PLP)脱氨
胺化
NH2磷酸毗哆胺
(PMP)
引.。