有机合成金点子-esterification_of_aldehydes_with_phenols

有机合成中的可持续化学方法可持续化学方法在有机合成中的应用随着社会的发展，对可持续发展的需求越来越迫切。

在化学领域，有机合成是一项重要的研究领域，也是促进可持续发展的一个关键环节。

本文将探讨有机合成中的可持续化学方法，并讨论它们的应用和优势。

一、催化剂的应用催化剂在有机合成中起到了至关重要的作用。

它们可以提高反应速率，降低反应温度和能量消耗，并且可以在反应过程中进行多次循环使用。

常见的有机合成催化剂包括金属有机框架（MOFs）、金属-有机框架化合物（PCN）等。

这些催化剂能够高效地催化有机物之间的反应，同时降低废物产生，提高合成效率。

二、溶剂替代有机合成中常用的溶剂往往具有毒性，并且很难降解。

为了减少对环境的污染，研究人员提出了许多可持续的替代溶剂。

例如，使用水或者可再生的溶剂，如生物质溶剂，可以显著减少对环境的影响。

此外，超临界流体也是一种可持续的溶剂选择，它具有低粘度和高扩散性，可提高反应速率和选择性。

三、生物催化生物催化是利用酶和细胞完成有机合成反应的一种方法。

与传统的化学合成相比，生物催化可以在温和的条件下进行，并且能够选择性地合成特定的产物。

此外，生物催化还具有高效性和可再生性的优点。

因此，生物催化在有机合成中被广泛应用，例如酶促反应、微生物发酵等。

四、可再生原料可再生原料是指从生物质、废弃物和二氧化碳等可再生资源中提取的化学物质。

与传统的石油化学品相比，可再生原料具有更低的碳足迹和更好的环境可持续性。

通过将可再生原料与可持续化学方法相结合，可以实现对环境的进一步保护，并促进经济可持续发展。

五、绿色能源的应用绿色能源在有机合成中的应用可以减少对传统化石燃料的依赖，降低二氧化碳排放。

太阳能、风能等可再生能源被广泛应用于有机合成中的能源供应。

此外，也有人研究利用微生物反应器或者电化学方法生成能源，以进一步提高合成过程的可持续性。

综上所述，可持续化学方法在有机合成中的应用具有重大意义。

通过催化剂的应用、溶剂替代、生物催化、可再生原料的利用以及绿色能源的应用，可以减少化学合成过程中对环境的污染，降低能源消耗，并实现可持续发展的目标。

有机合成中的合成策略和方法有机合成是有机化学领域中的重要研究方向，旨在通过化学反应将简单的有机分子转化为复杂的有机物。

在有机合成中，采用合适的合成策略和方法是关键，能够有效地提高合成的效率和产率。

本文将介绍几种常见的有机合成策略和方法，包括递增法、递减法、退火法、催化法等。

1. 递增法递增法是一种常见的有机合成策略，它通过将较简单的有机分子逐渐引入反应体系，并进行连续的化学反应，逐步构建目标分子的结构。

递增法在有机合成中应用广泛，能够实现复杂有机物的高效合成。

例如，合成一种新型杂环化合物的目标有机物A，可以从简单的起始材料B开始，通过一系列反应逐渐引入C、D等中间体，最终得到目标有机物A。

这一过程中，每一步反应都应基于充分的反应条件和选择合适的试剂，以确保产物的质量和产率。

2. 递减法递减法是与递增法相反的一种有机合成策略，它通过将复杂的有机分子逐渐去除其中的功能基团或键，最终得到目标化合物。

递减法常用于目标分子结构中特定官能团的构建。

例如，合成一种具有特定官能团的有机物A，可以从一个复杂的有机分子B开始，通过一系列反应逐渐去除其中的其他官能团，最终得到目标有机物A。

在递减法中，需要选择合适的试剂和反应条件，确保每一步反应的选择性和效率。

3. 退火法退火法是一种常见的有机合成方法，它通过加热有机分子使其发生结构变化，常用于构建环状化合物或调整立体结构等。

例如，合成一种含环有机物A的目标化合物，可以选择一个具有适当官能团的有机分子B作为起始材料，通过退火反应将B分子内部的特定官能团进行环化重排，最终得到目标化合物A。

退火法在有机合成中常用于构建芳香环、杂环等结构。

4. 催化法催化法是一种常用的有机合成方法，它利用催化剂促使反应发生，从而提高反应效率和产率。

催化法广泛应用于多种有机合成反应中，如氢化、酰化、羰基化反应等。

例如，合成一种特定有机物A，可以选择一个合适的催化剂C，将起始材料B与适当的反应物进行反应，在催化剂的作用下，促使反应发生，并得到目标有机物A。

NOTE/joc CuI-Nanoparticles-Catalyzed Selective Synthesis of Phenols,Anilines, and Thiophenols from Aryl Halides in Aqueous SolutionHua-Jian Xu,*,†,‡Yu-Feng Liang,†Zhen-Ya Cai,†Hong-Xia Qi,†Chun-Yan Yang,†and Yi-Si Feng*,†,‡†School of Chemical Engineering,Hefei University of Technology,Hefei230009,People's Republic of China‡Anhui Key Laboratory of Controllable Chemistry Reaction&Material Chemical Engineering,Hefei230009,People's Republic of China b Supporting InformationP henols,anilines,and thiophenols are important building blocks for constructing natural products,pharmaceutical and medicinal compounds,as well as in polymers and materials.1-3 The development of a mild and highly efficient method for synthesis of them over classical protocols has gained considerable attention in synthetic chemistry.Recently,several efficient palladium/phosphine-catalyzed processes have been developed for selective formation of phenols,4anilines,5and thiophenols.6 However,the replacement of palladium with less expensive copper(I)salt as catalyst would be allowed for economic benefits and low toxicity issues.The development of a cheaper system enabling the hydroxylation,7amination,8and thiolation9of aryl halides has become an important goal.More recently,a highly efficient copper-catalyzed procedure for the direct hydroxylation of aryl halides in the presence of ligands was disclosed by You7b and Taillefer7c independently and research showed that a well-defined ratio of water/organic solvent was the key factor,whereas water alone was inefficient.It is well-known that water is the most economical and environmentally friendly solvent in the world.10 Organic solvents contributed the largest amount of“auxiliary waste”in most chemical productions.11Very recently,efficient copper-mediated and ligand-assisted catalytic systems for direct conversion of aryl halides into phenols7f,g or anilines8a,b in water have been developed.Ma developed a protocol for thiophenols involving CuI-catalyzed coupling of aryl iodides with sulfur and subsequent reduction.9Unfortunately,all the above catalytic reactions are inefficient in neat aqueous medium in the absence of ligands.Metal nanoparticles have drawn much attention due to the advantages offered by these“semi-heterogeneous catalysts”.The characteristics of heterogeneous catalysis(recovery and re-cyclability)and those of homogeneous catalysis(relatively low catalyst loadings and good selectivity)were combined in nano-particles catalyst.In addition,because of their large surface area, metal nanoparticles usually showed high reactivity under mild conditions.12Thus,transition metal nanoparticles have been used widely as catalysts for organic synthesis.13Herein,we disclosed a very simple,efficient,ligand-free CuI-nanoparticles-catalyzed selective synthesis of phenols with water as the solvent under very mild conditions.14To our surprise,the coupling reaction gave selectively anilines when NH33H2O was added into the system.And thiophenols would be obtained selectively after reduction appending sulfur powder.To the best of our knowledge,there are no reports on this interesting chemoselec-tive arylation.The study was initiated by an investigation of hydroxylation of iodobenzene with CuI nanoparticles in water without any ligands.As shown in Table1,tetra-n-butylammonium hydroxide was used as the base at60°C with CuI nanoparticles as the catalyst(1.5mol%)in water(Table1,entry1),and the reaction gave selectively phenol in97%yield,the corresponding sym-metric ether appearing in only0.3%yield.When the base was altered to KOH,CsOH,Me4NOH,and Et4NOH,low yields were obtained(Table1,entries2-5).The copper(I)salts such as CuBr,CuCl,Cu2O,and CuI were found to be inferior to CuI nanoparticles(Table1,entries6-9).Control experiments confirmed that no conversion occurred without catalyst(Table1,Received:December18,2010entry 10).Low yields were obtained when the reaction time,temperature,or amount of CuI nanoparticles were reduced (Table 1,entries 11-14).The optimal conditions of 1.5mol %of CuI nanoparticles,3.0equiv of n Bu 4NOH in water at 60°C were used for further investigations.With this e fficient system in hand we next extended the scope of the substrate to various aryl iodide derivatives (Table 2).We found that the reaction was applicable to a broad range of derivatives and was not a ffected strongly by electron-donating or electron-withdrawing groups.But,the reactions seemed to be sensitive to the steric hindrance on the substrate.For example,1-chloro-2-iodobenzene was hydroxylated under optimized con-ditions,only 47%isolated yield was obtained.Fortunately,the reaction was accelerated signi ficantly at elevated temperature and longer reaction time.Almost quantitative conversions were obtained from 4-iodobenzoic acid and 2-iodobenzoic acid to the corresponding products.Although aryl bromides are less reactive than aryl iodides,the greater interest for industrial applications fixed our attention.In spite of the slightly higher temperature that was needed,a series of phenols were generated from activated aryl bromides (Table 3).We only obtained a few phenols whose yields are very close to the catalyst loading (Table 1,entries 16-20)with bromobenzene as substrate.The yield decreased with reactiontemperature elevating,probably because n Bu 4NOH decom-posed at higher temperature (Table 1,entry 19).However,we were able to obtain phenol in good yield (78%)when the amount of catalyst was increased to 110mol %(Table 1,entry 20).This method was extended successfully to aryl bromides with elec-tron-donating substituents such as p -or o -methyl and p -,or o -methoxy.1-and 2-bromonaphthalenes were also converted selec-tively into the corresponding naphthols under these conditions.Inspired by metal-catalyzed chemoselective N -or O -arylations,15we wondered whether N -arylation would take place when aqueous NH 3solution was added into the system with existing N,O nucleophilic competition.To our delight,the N -arylation readily occurred even at room temperature,and the product of O -arylation was detected in small quantity (<3%).Next,the scope of aryl iodides was investigated for the N -arylation reaction with aqueous ammonia at room temperature inTable 1.Optimization of Hydroxylation of Aryl Halides Catalyzed by CuI Nanoparticles in Water aentry X [Cu](mol %)base T /°C yield/%b 1I CuI(np(1.5))n Bu 4NOH 60972I CuI(np(1.5))KOH 60573I CuI(np(1.5))CsOH 60634I CuI(np(1.5))Me 4NOH 60795I CuI(np(1.5))Et 4NOH 60876I CuBr(10)n Bu 4NOH 60197I CuCl(10)n Bu 4NOH 60168I Cu 2O(10)n Bu 4NOH 60159I CuI(10)n Bu 4NOH 603310I n Bu 4NOH 60trace 11I CuI(np(1.5))n Bu 4NOH 508012I CuI(np(1.0))n Bu 4NOH 607113I CuI(np(1.0))n Bu 4NOH 808314c I CuI(np(1.5))n Bu 4NOH 607515d Br CuI(np(10))n Bu 4NOH 60trace 16d Br CuI(np(10))n Bu 4NOH 801117d Br CuI(np(50))n Bu 4NOH 804218d ,e Br CuI(np(50))n Bu 4NOH 804519d Br CuI(np(50))n Bu 4NOH 902720dBr CuI(np(110))n Bu 4NOH 807821d ,eClCuI(np(110))n Bu 4NOH8012aReaction conditions:halogenated benzene (1.0mmol),base (3.0equiv),H 2O (2.0mL)under N 2for 24h.b Determined by GC.cReaction time is 15h.d Reaction time is 48h.e With 5.0equiv of n Bu 4NOH.np =nanoparticles.Table 2.Hydroxylation ofAryl Iodides Catalyzed by CuINanoparticles in Water aaCuI nanoparticles (1.5mol %),Ar -I (1.0mmol),40%n Bu 4NOH aq (2.0mL/3.0equiv)at 60°C under N 2for 24h;isolated yield.b At 80°C for 36h.Table 3.Hydroxylation of Aryl Bromides Catalyzed by CuI Nanoparticles in Water aaCuI nanoparticles (1.5mol %),Ar -Br (1.0mmol),40%n Bu 4NOH aq (2.0mL/3.0equiv)at 80°C under N 2for 48h;isolated yield.b With 110mol %of CuI nanoparticles,n Bu 4NOH 40%aq (3.3mL/5.0equiv).water (Table 4).In general,all the aryl iodides gave the correspond-ing anilines with good to excellent yields.Ortho substituents had no obvious e ffect on yields of products to some extent,and a variety of functional groups could be tolerated in the reaction.Although little p -nitroaniline was detected when p -nitrobro-mobenzene was reacted with aqueous ammonia at room tem-perature,73%yield was obtained when the reaction was carried out at 80°C for 48h.Futhermore,p -nitroaniline was obtained with 87%yield when 3.0mol %of CuI nanoparticles and 10.0equiv of NH 3were applied.As shown in Table 5,all the examined aryl and heteroaryl bromides coupled with aqueous ammonia to a fford the corresponding anilines with good to excellent yields.On the other hand,aryl bromides bearing electron-donating substituents were less e ffective.In addition,the reactivity of aryl chlorides decreased dramatically in the present system.16We were pleased to observe that the coupling reaction produces selectively thiophenols after subsequent reduction when sulfur powder was added instead of aqueous ammonia (Table 6).17Aryl thiols were obtained with both inactivated and activated aryl iodide derivatives.No matter if the aryl iodides were electron-rich,electron-poor,or sterically hindered,all of them a fforded good to excellent yields.Moreover,aryl thiols of high yield were obtained with aryl bromides bearing electron-withdrawing groups.Low conversions occurred for inactivated aryl bromides.Since chemoselective N -arylation and S -arylation were accom-plished as opposed to O -arylation,a competitive experiment was performed to check out which arylation reaction would occur when the three substrates existed at the same time (Scheme 1).Under the standard conditions (see SI),iodobenzene was reacted in the presence of both NH 33H 2O and S,thiophenolTable 4.CuI-Nanoparticles-Catalyzed Amination of ArylIodides withNH 33H 2O at Room Temperature in Water aaCuI nanoparticles (1.5mol %),Ar -I (1.0mmol),40%n Bu 4NOH aq (1.3mL/2.0equiv),commercial 28%aqueous NH 3(5.0equiv)at room temperature (25°C)under N 2for 24h;isolated yield.b Reaction time is 48h.c At 45°C.d 4,40-Diiodobiphenyl as substrate,commercial 28%aqueous NH 3(10.0equiv).Table 5.CuI-Nanoparticles-Catalyzed Amination of Aryl Bromides aaCuI nanoparticles (3.0mol %),Ar -Br (1.0mmol),40%n Bu 4NOH aq (1.3mL/2.0equiv),commercial 28%aqueous NH 3(10.0equiv)at 80°C under N 2for 48h;isolated yield.Table 6.CuI-Nanoparticles-Catalyzed Synthesis of Thiophenols from Aryl Halides in Water aaCuI nanoparticles (1.5mol %),Ar -X (1.0mmol),40%n Bu 4NOH aq (1.3mL/2.0equiv),sulfur power (3.0equiv)at 40°C under N 2for 24h;isolated yield.b At room temperature (25°C).c With 3.0mol %CuI nanoparticles at 80°C for 48h.Scheme 1.Experiment of Intermolecular CompetitionScheme 2.One-Pot Synthesis of 4-Aminophenol from 1-Bromo-4-iodobenzenewas formed selectively after reductive step,proving the order ofS >N >O.Aminophenols constitute a common structural motif in var-ious potentially useful therapeutic agents and drug candidates.18The similarity in conditions between N -arylation and O -arylation suggested that the present protocol could be used as a tandem reaction,and this was indeed the case (Scheme 2).The synthesis of 4-aminophenol was achieved by hydroxylation of the C -I bond of 1-bromo-4-iodobenzene,followed by amination of the C -Br bond on increasing the temperature and reaction time.It was a heterogeneous process and the catalyst was recyclable with slight loss of activity (Table 7).19After completion of amination of iodobenzene,the catalyst was recovered from the reaction mixture by centrifugation and reused for the fresh reaction and only a slight decrease in catalytic activity was observed.In addition,in the TEM analysis of CuI nanoparticles,interestingly,the shape and size of the nanoparticles remainedunchanged before and after the reaction (Figure 1a -c).Likewise,the powder X-ray di ffraction analysis exhibited identical peaks for both the fresh and recovered CuI nanoparticles (Figure 1d,e).In conclusion,we have demonstrated that selective O -arylation,20N -arylation,and S -arylation could be achieved in water without assisted ligand at relatively mild conditions (no higher than 80°C).4a A variety of aryl iodides and bromides could be coupled with available n Bu 4NOH,NH 33H 2O,and S in this simple and e fficient protocol to give the corresponding products in high yields.The competition experiment showed that S had the best reactivity.Furthermore,the catalyst could be reused for three cycles with slight loss of its activity.’EXPERIMENTAL SECTIONGeneral Procedure for Hydroxylation of Aryl Iodides.An oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with CuI nanoparticles (1.5mol %,2.9mg),the aryl iodides if a solid (1mmol).The tube was evacuated and backfilled with nitrogen.Under a counter flow of nitrogen,aryl iodides if a liquid (1mmol,1equiv)and degassed 40%tetra-n -butylammonium hydroxides water solution (2.0mL)were added.The tube was sealed and the mixture was allowed to stir at 60°C for 24h.The reaction mixture was then allowed to cool to ambient temperature,then 10mL of ethyl acetate and 1mL of HCl (37%)were added.For the general workup and detailed experi-ments,please see the Supporting Information.’ASSOCIATED CONTENTbSupporting Information.Preparation of the catalyst,general synthetic procedures,and characterization of products.This material is available free of charge via the Internet at .’AUTHOR INFORMATIONCorresponding Author*E-mail:hjxu@ and ysfeng@.’ACKNOWLEDGMENTWe gratefully acknowledge financial support from the Na-tional Natural Science Foundation of China (Nos.20802015,21072040,21071040).We thank Yong-Qiang Zhao in this research group for reproducing some results in Tables 2-6.’REFERENCES(1)For phenols:(a)Tyman,J.H.P.Synthetic and Natural Phenols ;Elsevier:New York,1996.(b)Rappoport,Z.The Chemistry of Phenols ;Wiley-VCH:Weinheim,Germany,2003.(2)For anilines:(a)Weissermel,K.;Arpe,H.J.Industry Organic Chemistry ;Wiley-VCH:Weinheim,Germany,1997;(b)Lawrence,S.A.Amines:Synthesis Properties and Application ;Cambridge University Press:Cambridge,UK,2004.(3)For thiophenols:(a)Thuillier,A.;Metzner,P.Sulfur 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有机合成中的催化方法催化方法在有机合成领域扮演着重要的角色，能够加速反应速率并提高产物收率。

本文将探讨几种常见的有机合成中的催化方法，并讨论它们在实际应用中的优点和局限性。

一、金属催化剂金属催化剂是有机合成中最常见和最广泛使用的催化方法之一。

金属催化剂可以通过活化底物中的化学键来促进反应。

其中，贵金属如铂、钯、铑、钌等常被用作催化剂，因为它们具有良好的催化活性和选择性。

金属催化剂的一个重要应用是氢化反应。

氢化反应通常用于还原酮、醛、烯烃或芳香化合物中的双键。

铂和钯催化剂在氢化反应中表现出色，由于它们能够有效地催化氢气分子的加成与底物中的双键。

二、有机催化剂有机催化剂是近年来兴起的一种有机合成催化方法。

相比于金属催化剂，有机催化剂更加可控和环境友好。

有机催化剂可以通过作用于底物中的特定官能团来促进反应。

其中，酶类催化剂如Lipase和酶类纳米颗粒等常被用于生物催化反应。

近年来，卡伦研究小组开发了类似金属的有机催化剂。

这种新型有机催化剂具有与金属催化剂相似的活性和选择性，但不受金属催化剂中毒和成本等问题的限制。

三、羰基合成催化剂羰基合成催化剂主要用于合成酮和醛化合物。

常见的羰基合成催化剂包括Pauson-Khand反应中的钯催化剂、Wittig反应中的四氟硼盐和Wittig盐等。

羰基合成催化剂可以在温和的条件下有效催化羰基加成反应，它们可以提供高产率和高选择性。

此外，这些催化剂还可以通过调整催化反应的条件来得到不同结构的产物。

四、光催化剂光催化剂是近年来兴起的一种催化方法，其利用光能来激发底物中的电子从而促进反应。

光催化剂在有机合成中具有广泛的应用，如光氧化反应、光还原反应和光引发的环化反应等。

光催化剂的一个重要应用是光催化羧酸的合成。

例如，钛、铌等金属光催化剂可以通过光氧化反应将芳香羧酸转化为酸酐。

此外，光催化剂还可以在紫外光的作用下催化光引发的环化反应，合成复杂有机化合物。

总结：有机合成中的催化方法是加速化学反应的重要手段，金属催化剂、有机催化剂、羰基合成催化剂和光催化剂是其中常见的几种方法。

有机合成中的新策略与方法近年来, 有机合成领域不断涌现出新的策略与方法, 为有机化学家们提供了更多的选择和可能性。

这些新进展使得有机合成更高效、更绿色、更可持续, 有助于解决传统有机合成中的瓶颈问题。

以下将介绍几种新的有机合成策略与方法。

一、金属催化有机合成金属催化有机合成是一种利用金属催化剂促进有机反应的方法。

金属催化反应可以在较温和的条件下进行, 同时具有高效和选择性的优点。

例如, 钯催化的交叉偶联反应(Pd-catalyzed Cross-Coupling Reaction)在有机合成中得到了广泛应用。

这种反应可以将碳-碳键或碳-氮键形成新的键, 极大地拓展了有机合成的范围。

二、可再生原料的利用随着可再生能源的重要性日益凸显, 有机化学家们开始探索将可再生原料应用于有机合成中的新方法。

例如, 生物质转化为化学品的合成过程中, 基于碳-氧键活化的一系列反应被广泛研究。

这些反应可以将生物质转化为高附加值的有机化合物, 同时减少对传统石油资源的依赖。

三、光化学与电化学的应用光化学与电化学在有机合成中的应用正在成为新的研究热点。

光化学和电化学反应可以实现非常温和的条件下的反应控制, 同时还能节省能源。

例如, 光催化还原和光催化氧化反应能够在光照条件下完成, 避免了传统有机合成中需高温、高压条件下的不足。

四、多组件反应多组件反应(Multicomponent Reactions, MCRs)是一种将多个反应物一次性加入反应体系中, 经过多步反应形成目标产物的方法。

MCRs具有高效和多样性的特点, 在有机合成中具有重要应用价值。

例如, Ugi反应和Povarov反应等多组件反应已被广泛研究和应用。

总结有机合成中的新策略与方法为有机化学家们提供了更广阔的发展空间。

金属催化、可再生原料的利用、光化学与电化学的应用以及多组件反应等新策略与方法, 为有机合成的高效、绿色和可持续发展提供了坚实的基础。

随着科学技术的不断进步和创新, 我们相信将会有更多的新策略和方法出现在有机合成的研究领域, 为有机化学发展贡献更多的力量。

海克替啶合成工艺
海克替啶（Heptadine）是一种合成药物，其化学名称为N-(1-乙氧乙基)-3,4-二甲氧基苯胺，又名N-(1-乙氧乙基)-3,4-二甲氧基苯胺。

以下是海克替啶的一种合成工艺：
1. 首先，将3,4-二甲氧基苯胺与环氧氯丙烷在碱性条件下进行醚化反应，生成N-(2-氯乙氧)-3,4-二甲氧基苯胺。

2. 然后，将得到的N-(2-氯乙氧)-3,4-二甲氧基苯胺与乙醇在酸性条件下进行烷基化反应，生成N-(1-乙氧乙基)-3,4-二甲氧基苯胺，即海克替啶。

以上是海克替啶的一种合成工艺，具体的反应条件和步骤可能会因实际需要而有所不同。

在进行实验时，一定要严格遵守化学实验的安全规程，确保实验的安全进行。