胺化-Catalytic C–H amination- recent progress and future directions

Catalytic C–H amination:recent progress and future directions w

Florence Collet,Robert H.Dodd and Philippe Dauban*

Received (in Cambridge,UK)24th March 2009,Accepted 2nd June 2009First published as an Advance Article on the web 7th July 2009DOI:10.1039/b905820f

Recent developments in catalytic C–H amination are discussed in this feature article.The careful design of reagents and catalysts now provides e?cient conditions for exquisitely selective

intramolecular as well as intermolecular nitrene C–H insertion.The parallel emergence of C–H activation/amination reactions opens new opportunities complementary to those o?ered by nitrenes.

Introduction

Nitrogen is a key atom in nature,found in several well known natural product families such as amino acids,alkaloids,porphyrins and penicillins,where it is incorporated via biosynthetic pathways involving condensation reactions with a pre-installed oxygen functionality.1Moreover,nitrogen is ubiquitous in biology,with synthetic drugs generally containing more nitrogen than natural products.2Its ability to carry a positive charge,as well as to act as a hydrogen bond donor and/or acceptor,strongly in?uences the interaction between the medicinal agent and its target.In addition,the p K a s of amines are often in the range of physiological pH,a physical property essential for improving the bioavailability of drugs.

Finally,nitrogen is also important in material sciences,where its presence in the structures of polymers can have a profound e?ect on their physical,electronic or surface properties.3

In the context of the synthesis of natural products,bioactive compounds or materials,the development of novel C–N bond forming methodologies is an intensively investigated ?eld of the utmost importance.While classical transformations range from nucleophilic displacement of a leaving group to reductive carbonyl amination or imine alkylation,4newly discovered processes have mostly taken bene?t from the advent of transition metal catalysts,5and modern amination methods now include Buchwald–Hartwig C–N coupling,6hydroamination 7and diamination 8of ole?ns,and allylic amination (Scheme 1).9More fundamentally,the emergence of transition metal complexes has also helped to address the question of whether a hydrogen could be directly replaced by an amino group.Such a C–H functionalization process o?ers unique opportunities 10complementary to those provided by the above-mentioned reactions,all based on the transformation of a pre-installed functional group.This,however,requires ?nding suitable conditions for the generation of highly active

Institut de Chimie des Substances Naturelles,UPR 2301CNRS,Avenue de la Terrasse,91198Gif-sur-Yvette Cedex,France.

E-mail:philippe.dauban@https://www.docsj.com/doc/a713665678.html,rs-gif.fr;Fax:+33169077247;Tel:+33169824560

w This feature article is dedicated,on the occasion of his 70th birthday,to our friend and colleague Paul Mu ller,who has made pioneering studies in the ?eld of nitrene

transfers.Florence Collet

Florence Collet graduated from the Ecole Nationale Supe ′rieure de Chimie de Montpellier in 2006.During the course of her formation,she carried out a one-year industrial internship at GlaxoSmithKline in Harlow,where she was granted a GSK recognition bronze award.After completion of her Masters Degree,she is now a PhD fellow at the Institut de Chimie des Substances Naturelles under the super-vision of Dr Philippe Dauban

and Dr Robert Dodd on the development of catalytic C–H amination and its application to the synthesis of bioactive compounds.Outside the laboratory,she enjoys playing harp and piano,as well as travelling all around the

world.

Robert H.Dodd

Robert H.Dodd completed his BSc degree in chemistry at McGill University in Montreal in 1974,and his PhD at the University of British Columbia in Vancouver in 1979where he worked under the supervision of Alex Rosenthal in the area of carbohydrate and nucleo-side chemistry.After post-doctoral studies at the University of Geneva,he joined the Institut de Chimie des Substances Naturelles as a research associate in the group of Pierre Potier.He is pre-sently a First Class Research Director at the ICSN.His research interests include the development of new synthetic methodology towards nitrogen-containing heterocycles and com-plex amino acids,and application of these methodologies to the preparation of natural and bio-active compounds including CNS agents,antibiotics,antimitotics and GPCR ligands.

FEATURE ARTICLE https://www.docsj.com/doc/a713665678.html,/chemcomm |ChemComm

but su?ciently mild species to induce selective C–H functiona-lization,a real challenge given the high energy and the ubiquity of C–H bonds in organic substrates.Paradoxically,while adequate oxygenases for selective C–H hydroxylation do exist in nature,the analogous direct nitrogen transfer has not been found in any biosynthetic pathway so far.2a

The ?rst examples of metal-mediated C–H amination date back to the late 60s with the reports of Kwart and Kahn,11D.S.Breslow and Sloan,12and Turner et al .13More attention from the organic community was,however,given to the studies involving iminoiodanes published by R.Breslow and Gellman in the early 80s.14Their seminal paper 14b on the capacity of iron porphyrin or rhodium acetate to e?ciently catalyze intramolecular C–H amination,together with that of Mansuy et al.documenting the intermolecular version,15paved the way for future investigations.It also clearly demonstrated the potential of nitrene C–H insertion for the synthesis of nitrogen-containing products,a ?eld that has considerably expanded in the last decade with the development of mild,convenient procedures for the generation of nitrenes.

The reaction of commercially available hypervalent iodine reagents with various NH 2-containing substrates has therefore led to the discovery of elegant and e?cient methodologies that has culminated with the total synthesis of Tetrodotoxin.16

These early but successful results have been summarized in several reviews that witness the growing impact of C–H amination in organic chemistry.17This feature article will therefore emphasize more particularly the latest developments made within the last three years.These have con?rmed that intramolecular C–H amination now belongs to the arsenal that synthetic chemists have at their disposal for C–N bond formation.Recent studies have moreover allowed to overcome some,but not all,of the limitations of catalytic hypervalent iodine-mediated nitrene C–H insertions.More interestingly,new aminating protocols involving C–H activation have emerged in parallel.These transformations,with the C–H bond being broken in the ?rst step of the catalytic cycle,di?er mechanistically from the nitrene-based methodologies,(Scheme 2).The ‘‘inner-sphere’’mechanism thus tends to give selectivities complementary to those induced by the ‘‘outer-sphere’’one.17f ,18

Intramolecular C–H amination

Based on Breslow’s pioneering study,Espino and Du Bois have devised elegant solutions for the selective insertion of nitrogen into various C–H bonds.These C–H aminations involve the regioselective internal delivery of a nitrene generated by using a combination of PhI(OAc)2and magnesium oxide in the presence of a rhodium(II )catalyst (Scheme 3).Thus,the use of carbamates as nitrene precursors leads to oxazolidinones via C–H insertion at the b -position,19while in the case of sulfamates,the reaction generally occurs at the g -position,a?ording homologous 6-membered rings.20With both substrates,it is recognized that the reaction takes place via a concerted asynchronous insertion of a singlet metal-bound nitrene,but an extremely fast recombination of radical species (estimated lifetime:200fs)cannot be ruled out.This scenario,while still hypothetical,is supported by DFT studies,21physical organic experiments (Hammett studies:r =à0.55(vs.s +),kinetic isotope e?ect of 1.9?0.2,absence of ring opened products using a cyclopropyl radical clock)17k ,20d and the stereospeci?c nitrene insertion with retention of con?guration in the case of 1.Recent kinetic studies 20d have also revealed that the process is ?rst-order with respect to both PhI(OAc)2and the sulfamate.This result suggests the initial rate-limiting formation of an iminoiodane,but this remains

a

Scheme 1C–N bond forming

reactions.

Scheme 2General mechanisms of C–H

amination.

Philippe Dauban

Philippe Dauban graduated

from the Ecole Supe ′rieure de Chimie Industrielle de Lyon in 1991.He then received his PhD from the Universite ′Paris XI in 1996,by working under the direction of Dr Robert Dodd.After postdoctoral studies with Professor Jean-Claude Fiaud as a Rho ?ne-Poulenc fellow,he obtained a permanent position at the Institut de Chimie des Sub-stances Naturelles where he was recently named CNRS Research Director.His ?elds

of research interest lie in the development of new catalytic methodologies for C–C and C–N bond formation,and their application in synthesis and medicinal chemistry.A former soccer player,he is now strongly involved in ‘‘quille aveyron-naise’’.

matter of debate since this intermediate has not been detected so far.Importantly,the chemoselectivity observed in intra-molecular C–H aminations is excellent.As a consequence of electronic e?ects,the preferred reacting positions are a -ethereal,tertiary and benzylic sites but functionalizing a secondary C–H bond is also feasible.19,20The chemoselectivity can,however,be less predictable with unsaturated compounds.While intramolecular allylic amination occurs e?ciently when applied to cyclic substrates,22ole?n aziridination generally competes with the latter in acyclic compounds.20d ,23In all cases and as already observed in diazo-derived carbene chemistry,24the rhodium catalyst ligands strongly in?uence the course of nitrene delivery,benzylic C–H amination being,for example,highly disfavored with Rh 2(tpa)4.20Recent developments

In order to improve the scope of intramolecular C–H aminations,attention has been recently paid to the design of either new catalysts or nitrene precursors.To this end,Du Bois et al.have developed a more robust rhodium(II )catalyst,Rh 2(esp)26,composed of two identical bidentate ligands derived from m -benzenedipropionic acid.25Its e?ciency is such that high conversion can be reached with loadings ranging from 0.15to 1mol%.But more interestingly,its use allows extension of intramolecular C–H amination to ureas,guanidines 25b and sulfamides 25c (Scheme 4).Sulfamates,however,remain the most useful nitrene precursors,because not only do they often a?ord crystalline compounds,but they also o?er unique synthetic opportunities (vide infra ).Moreover,while they were initially used for the preparation of 1,3-difunctionalized products,it has been recently demonstrated that they can give access to 1,2-diamines by using a sulfamate derived from hydroxylamines of type 13.26

The question of catalytic asymmetric intramolecular C–H amination has also been addressed by the design of new ligands.This was met with limited success in early studies,with enantioselectivities of only up to 66%obtained using chiral rhodium(II )carboxylate complexes.27Higher ee’s,typically in the 60–99%range,have since been recorded with the cleverly conceived rhodium(II )carboxamidate complex,Rh 2(S -nap)415(Scheme 5).28This is the ?rst example of the use of an amide-derived Rh(II )complex in C–H amination,which opens new directions for the design of chiral ligands.

The origin of this breakthrough can be traced back to a redox

potential su?ciently high to prevent catalyst deactivation by the hypervalent iodine-mediated one-electron oxidation.A point worth mentioning is the chemoselectivity observed with 15in the case of allylic substrates for which C–H amination rather than aziridination is highly favored.

The results described above clearly indicate that rhodium complexes are the catalysts of choice for intramolecular C–H aminations,although other metals can be used for this purpose,particularly ruthenium porphyrins.29Chiral versions of the latter were found to induce asymmetric nitrene

C–H

Scheme 4C–H amination using Rh 2(esp)26

.

Scheme 5Enantioselective intramolecular C–H

amination.

Scheme 3Intramolecular C–H amination with carbamates and sulfamates.

insertions with ee’s up to 87%.29a However,further screening of complexes was hampered by the need to prepare expensive chiral porphyrin ligands.Non-porphyrin catalysts were considered 30with limited success until Blakey et al.demonstrated that cationic ruthenium(II )pybox complexes of type 16e?ciently catalyze intramolecular C–H amination with enantio-and chemoselectivities comparable to those induced by 15.30b The key to the success of the reaction is the use of a catalytic quantity of a silver salt with a non-coordinating anion necessary to generate an active cationic species,since neutral complexes such as 16proved to be of limited reactivity.Nevertheless,despite these achievements and regardless of the metal involved,these asymmetric intramolecular C–H aminations remained con?ned to benzylic and allylic positions.Within today’s highly sensitive issue of sustainable chemistry,a limitation attributed to the hypervalent iodine-mediated generation of nitrene is the release of a stoichiometric amount of PhI.As a greener alternative,Lebel et al.have proposed the use of N -tosyloxycarbamates,prepared in two steps from the corresponding alcohols (Scheme 6).31The nitrene is thus generated by treatment with an inorganic base in the presence of a rhodium(II )complex,the released tosylate salt being easily removed by a simple aqueous work-up.The reported results appear to be comparable to those previously described with hypervalent iodine.In particular,similar trends in chemo-selectivity are observed and good enantioselectivities up to 82%have been obtained with a chiral rhodium catalyst.32Also of note is a rare example of nitrene C–H insertion into a primary position.A possible extension of this chemistry would be its application to sulfamates provided that the question of the preparation of the starting materials can be solved.

Another green alternative that would undoubtedly be even more atom-economical and environment-friendly,involves azides.These were historically the ?rst reagents to be used for the generation of nitrenes under either thermal or photo-chemical conditions 17a ,33but surprisingly,they have not often been exploited in the context of transition metal-catalyzed C–H amination.34Recent intramolecular reactions have emerged,35especially devoted to the preparation of indoles via rhodium(II )decomposition of vinyl-35a and arylazides (Scheme 7).35b While the net result of these transformations is a formal nitrene C–H insertion into a Csp 2–H bond,they in fact take place via stepwise electrophilic additions.More interestingly,they constitute a rare case of nitrene generation from azides mediated by rhodium complexes.This stands in contrast to previous experiments conducted with electron-

de?cient azides,which proved to be stable under these conditions.31a

Ruthenium complexes 34a and cobalt porphyrins 36have been demonstrated to be more active catalysts in this context,a reactivity that has been recently applied to intramolecular Csp 3–H aminations starting from arylsulfonyl azides for the preparation of cyclic sulfonamides.37Recent applications in total synthesis

Several previous applications of intramolecular C–H amination have already demonstrated its synthetic utility 17a and recent examples have con?rmed its emerging status as a standard C–N bond forming reaction.The sometimes-called ‘‘Du Bois reaction’’has thus been applied to the preparation of simple nitrogen-containing molecules such as (à)-cytoxazone 29,38(+)-conagenin 30,aminopropanediols 31or pachastrissamine 32,39while its use for phakellin alkaloid assembly 40has had more limited success (Scheme 8).More impressive are the selective C–H functionalizations observed in the case of complex advanced intermediates or natural product analogs (Scheme 9).The synthesis of (+)-gonyautoxin 335illustrates the power of C–H amination,though the nitrene addition does not occur here via the usual C–H insertion.41It leads to the selective formation of the tricyclic sca?old 37,resulting from acidic quenching of a hypothetical zwitterionic intermediate that induces the concomitant formation of an alkene suitably located for further oxidations.No competitive C–H amination occurs at the other b C–H bond despite its cis

arrangement.

Scheme 6Intramolecular C–H amination using N -tosyloxy-

carbamates.

Scheme 7Intramolecular C–H amination using

azides.

Scheme 8Intramolecular C–H amination in natural product synthesis.

Comparably good regioselectivities have also been observed in intramolecular C–H amination applied to deoxoartemisinin-derived carbamate 38and sulfamate 40.42Such reactions allow a direct access to selectively modi?ed analogs of potential biological interest.

Sulfamates o?er additional opportunities that ?rst rely on their ability to a?ord C–H aminated products at a -ethereal positions.C–H amination thus leads to N ,O -acetals likely to react subsequently with various nucleophiles.20b ,c This has been applied,among other targets,17a to the total synthesis of (+)-saxitoxin 43and,more recently,to an approach to the complex alkaloid aconitine.44Starting from the model substrate 42,oxidative C–H amination a?ords selectively the N ,O -acetal 43(Scheme 10).Treatment with BF 3áOEt 2then leads to 45as a single diastereoisomer after thermo-dynamically-controlled arene addition to the in situ generated iminium 44.

On the other hand,cyclic sulfamidates can react with various types of nucleophiles at the C–O bond after activation by introduction of an electron-withdrawing group on the nitrogen.20a ,45This electrophilic reactivity combined with that of aminals has been applied to an elegantly devised synthesis of polysubstituted piperidines of type 46.46a The strategy is based on iterative C–H aminations,the regioselectivity of which is governed by conformational factors.46b ,c Successive appropriate nucleophilic displacements following the C–N bond forming reactions thus allow functionalization of the piperidinyl core.

Intermolecular C–H amination

While a high degree of chemo-and regioselectivity can be assured by the intramolecular delivery of nitrene,devising a similar intermolecular C–H bond discriminating process is much more challenging.In C–H activation-based transformations,elegant solutions have arisen from application of the chelate

e?ect that brings the metal into the vicinity of the C–H bond

to be cleaved (vide infra ).10Such a chelation has,however,been rarely envisaged in C–H insertion,where the metal does not interact directly with the substrate.47E?ciency is also an issue to address due to the high reactivity of metallanitrene,a drawback circumvented in intramolecular C–H amination wherein the reacting centers are in close proximity.Finally,the formation of products resulting from over-oxidation must also be minimized.Consequently,several early examples of intermolecular nitrene C–H insertions were successful only when substrates were used in large excess.17a ,f These reactions were,moreover,often directed towards the amination of ‘‘activated’’C–H bonds,i.e.benzylic and allylic positions of lower bond dissociation energy,which display higher reactivity vis -a `-vis the electrophilic metallanitrene.

The ?rst signi?cant progress in this direction arose from the studies of Che et al.who demonstrated the high capacity of ruthenium and manganese porphyrin complexes to catalyze the amidation of benzylic and allylic C–H bonds (Scheme 11).48High yields up to 86%were reported starting from a stoichiometric amount of these substrates.Moreover,C–H amination of cyclohexene,but not of 3-hexene or allylbenzene,proved to be chemoselective.48a Asymmetric transformations have also been described with ee’s up to 56%.48c A stepwise mechanism has been proposed,with the formation of carboradical intermediates following H-abstraction by an imidometal species (kinetic isotope e?ects ranging from 6.1to 11).48d More fundamentally,Che has been the ?rst to demonstrate the possibility of generating in situ the somewhat capricious iminoiodanes,48a a new procedure that paved the way for future intermolecular nitrene transfers from a variety of nitrogen precursors.As an illustration of this important ?nding,C–H amination has been found to occur with carboxamides,although

these

Scheme 9Selective C–H amination with complex

substrates.

Scheme 10Synthetic opportunities provided by sulfamates.

are known to undergo Hofmann rearrangement with hyper-valent iodine reagents.49

Recent developments

Despite these signi?cant achievements,improvements were needed in terms of e?ciency,selectivity and scope in order to dispose of a general method for intermolecular C–H amination.To this end,several transition metals have been thoroughly investigated.While cobalt porphyrin,50zinc(II)51 or iron(II)52have been shown to catalyze such intermolecular C–H functionalization,albeit with limited scope and modest e?ciency,the results reported with silver(I),copper and, especially,rhodium(II)complexes have been more noteworthy. Initially found to catalyze intramolecular C–H amination of carbamates and sulfamates,53a dinuclear silver(I)complexes50 have also proved to be active for the intermolecular amination of various hydrocarbons(Scheme12).53b Primary,secondary and tertiary benzylic positions,as well as cyclic hydrocarbons, though necessarily used in excess,can thus be aminated with yields in the25–71%range.The dinuclear core,assured by the stacking of two4,7-disubstituted-1,10-phenanthroline ligands, has been found to be crucial for the catalytic activity and is probably one of the key factors for the proposed concerted insertion of a silver-bound nitrene.This stands in contrast to monomeric silver(I)-homoscorpionate complexes53,which operate through a stepwise radical pathway as suggested by the lower conversions observed in the presence of a radical inhibitor.54A noteworthy feature of catalyst53is its ability to mediate the amination of linear and branched alkanes54and 57,used as solvents of the reaction,with high regio-and chemoselectivities in favor of the tertiary position.This result can be considered as an important step towards the selective C–H functionalization of alkanes.

In combination with copper(I)salts,scorpionate ligands have also been shown to induce unexpected regioselective aminations in the case of alkylaromatics such as p-ethyltoluene.55 Nitrene insertion thus occurs at the secondary benzylic position,but also at the primary benzylic site,as well as at the terminal of the ethyl side-chain.The study also con?rmed the capacity of copper(I)complexes to catalyze C–H nitrene insertion using chloramine-T as previously observed by Taylor et al.,56thereby opening opportunities to develop e?cient green procedures since innocuous NaCl is the sole by-product generated in this case.

These results have been exploited by Bhuyan and Nicholas who reported an e?cient catalytic intermolecular C–H amination involving a stoichiometric amount of substrate and the commercially available Cu(CH3CN)4PF6catalyst.57Good yields up to77%were obtained provided,however,that the chloramine-T was previously dried.The reaction occurs at primary,secondary and tertiary benzylic positions,as well as at a-ethereal sites(Scheme13),but chemoselective allylic C–H amination has proved impossible so far.Although these experiments highlight the potential of chloramine-T as a C–H aminating agent,the e?ciency of the process remains lower than that involving hypervalent iodine reagents,as suggested by the study published within the same period and devoted to the copper-catalyzed amidation of cyclic ethers,58 as well as by those obtained with rhodium complexes (vide infra).The capacity of copper to catalyze C–H amination under a variety of oxidizing conditions has been largely documented in several other studies.Thus,halogenated and, more particularly,peroxide oxidants have been found to

be Scheme11Mn-and Ru-catalyzed intermolecular C–H

amination. Scheme12Silver-catalyzed intermolecular C–H

amination.Scheme13Copper-catalyzed intermolecular C–H amination.

suitable for generating aminating species.59The reaction generally occurs via radical intermediates and good yields are obtained,though only with 2–5equivalents of substrates.Nevertheless,these procedures are likely to complement metal–nitrene mediated amination since they have been applied to the insertion of primary or secondary sulfonamides and carboxamides.59c –e

More intriguing are the results that have recently emerged concerning ligand design.60The development of monoanionic b -diketiminates of type 67has allowed the isolation of the ?rst crystalline dicopper nitrene [(Me 3NN)Cu]2(m -NR)269by reaction with 3,5-dimethylphenylazide (Scheme 14).60a Slow dissociation in solution of a b -diketiminate copper fragment may generate a transient terminal copper–nitrene species,as suggested by cross-over https://www.docsj.com/doc/a713665678.html,e of the bulkier adamantylazide then proved even more striking,a?ording a similar dicopper nitrene complex 70,which undergoes an intramolecular nitrene insertion into one of the aromatic o -methyl groups to give 72.60b

Replacement of these o -methyls by an inert chloro atom thus prevents this intramolecular transformation from taking place and has therefore led to the elegant conception of a new type of copper(I )catalyst for intermolecular C–H amination using azides as nitrene precursors.The m -benzene analog of 71displays very good catalytic activity,since 2.5mol%of this complex induces the C–H functionalization of various hydro-carbons used in stoichiometric amounts,with yields ranging from 31to 82%.The mechanism has been investigated by theoretical calculations based on CASSCF methods that support a singlet open-shell ground state,60c contrary to DFT studies in favor of a triplet ground state.These extra-ordinary results pave the way to a better understanding of the species involved in metal–nitrene chemistry,which should help in the design of more reactive catalysts and/or nitrene precursors.As previously mentioned,azides also provide

opportunities for greener procedures.In the present case,they allow the introduction of nitrogen substituted by an alkyl group,thereby complementing the previous methodologies based on carbamate-,sulfonyl-and sulfamate-derived nitrenes.Finally,signi?cant progress in intermolecular C–H amination has also arisen in the case of rhodium catalysts through the design of either ligands or new types of nitrene sources.Initial noteworthy examples,including the seminal work of Mu ller et al.,61as well as the asymmetric versions developed by Hashimoto et al.,62and Reddy and Davies,32were based on the hypervalent iodine-mediated generation of nitrene from sulfonamides.Very good yields up to 95%and ee’s up to 94%were,however,secured only by the presence of an excess of substrate.Fruit and Mu ller thus made the ?rst observation that sulfamates can a?ord higher yields even with a stoichiometric amount of starting material.63Such a di?erence in reactivity has since then been clearly demonstrated by Du Bois et al .25a ,64

A combination of the aforementioned Rh 2(esp)26and trichloroethylsulfamate (TcesNH 2)75has been shown to give up to 74%yields of C–H aminated products,the protocol being even applicable to the preparation 15N-labeled compounds.The functionalization of secondary benzylic and tertiary positions is favored.In the case of products having multiple reactive sites,the regioselectivity is governed by a combination of electronic and steric factors,the more sterically accessible and/or electron-rich C–H bond being preferentially aminated as has also been observed in carbenoid chemistry (Scheme 15).17b Surprisingly,competition experiments have indicated that inter-and intramolecular C–H aminations exhibit opposite selectivities in some instances.Benzylic positions are thus favored over tertiary sites in the inter-molecular reaction,while the ratio is reversed in the intra-molecular version.This observation may suggest a di?erent mechanism for each reaction,a postulate,however,disproved by detailed mechanistic investigations reported by Mu ller

et al.,61and Fiori and Du Bois.64

Several data (stereospeci?c amination,Hammett analysis:r =à0.90and à0.73(vs.s +),no ring opening observed in the case of a cyclopropyl radical clock)indeed support the formation of an analogous rhodium-bound nitrene via the intermediacy of the presumed imino-iodane,which undergoes an asynchronous concerted

C–H

Scheme 14Structure and reactivity of copper–nitrene

complexes.Scheme 15Intermolecular rhodium-catalyzed C–H amination.

insertion.64This hypothesis,however,is somewhat contradicted by the unexpectedly large kinetic isotope e?ect of3.5?0.2found in the case of deuterated adamantane.61 The exceptional performance of6then encouraged Du Bois to develop a chiral version but this has met with limited success so far,the ee’s remaining in the20%range.By comparison,devising a chiral nitrene precursor may appear conceptually less appealing than the design of chiral ligands for the development of stereoselective nitrene transfer,since the chirality element will be present in a stoichiometric amount.Application of this strategy based on the design of chiral sulfur(VI)reagents analogous to sulfonamides has, however,led to unprecedented results.Sulfonimidamide-derived nitrenes thus display exceptionally high reactivity?rst revealed in transition metal-catalyzed aziridinations65and then con?rmed with the development of an e?cient diastereo-selective intermolecular benzylic C–H amination.66

The preparation of less sterically-demanding chiral ligands for the rhodium catalyst then allowed extension of the reaction to allylic substrates,as well as to simple alkanes.67The key to this success is the optimized combination of the optically pure sulfonimidamide(S)-82and the chiral rhodium catalyst Rh2((S)-nta)483,the ligand of which derives from L-alanine.

A strong matched e?ect results from their interaction,thus leading to intermolecular benzylic and allylic aminations with excellent yields and diastereoselectivities up to92and99%, respectively,starting from1equivalent of the C–H bond-containing substrate(Scheme16).Even cyclic hydro-carbons can be e?ciently functionalized under stoichiometric conditions.The chemoselectivity induced by chiral rhodium complexes is exceptional since no aziridines are formed in the case of allylic substrates,contrary to what is observed with Rh2(OAc)4,65b while products arising from multiple aminations or auto-oxidation to imines are not observed. Another point worth mentioning is the selectivity towards secondary benzylic and allylic sites as a consequence of the best compromise in terms of electronic and steric e?ects.By

contrast,branched alkanes such as2-methylbutane have been found to react at the tertiary position.

The nature of the interactions responsible for the high stereoselectivity observed are not yet clearly understood, although p-stacking between one or both aromatic groups of 82and the naphthoyl substituent of the rhodium catalyst83 are suggested by the low yields obtained with analogs devoid of these rings.In fact,the matched e?ect is so pronounced that practical kinetic resolution of racemic82is operating for benzylic C–H amination.An unexpected feature of this reaction is the need to also use a protic co-solvent,i.e. methanol,to assure the e?ciency of nitrene C–H insertion. In all the examples previously discussed in this review,inter-and intramolecular C–H aminations take place in common hydrocarbon or halogenated solvents such as benzene,toluene or dichloromethane.The role of methanol is unclear and presumably not limited to the simple solubilization of82, since one would expect solvolysis of the metallanitrene inter-mediate in the presence of such a protic source.Finally, gaining information concerning the origin of the high reactivity of the sulfonimidamide-derived nitrene is essential and would help to design more atom-economical precursors,one of the drawbacks of this process together with the release of PhI.

In this context of green chemistry,Lebel and Huard have demonstrated that the intermolecular process involving the aforementioned N-tosyloxycarbamates is indeed applicable, though an excess of substrate is necessary.31b,68Once again,and despite a kinetic isotope e?ect of5measured for d12-cyclohexane,greater than those usually recorded for such a mechanism,17i a concerted C–H insertion of a rhodium-bound singlet nitrene has been invoked based on the stereospeci?city of the amination,a Hammett analysis(r=à0.47(vs.s+)) and the study of a cyclopropyl radical clock.

Contrary to intramolecular C–H amination,most of the recent studies devoted to the intermolecular version have focused on methodological developments.The few synthetic applications reported in the literature so far were all related to the selective functionalization of steroids48c,69until a recent study of the formal synthesis of(à)-pancracine appeared.70 Within the context of his studies documenting the catalytic enantioselective amination of silyl enol ethers and ketene acetals,71Hashimoto et al.discovered a rare example of asymmetric allylic C–H amination in the case of

the Scheme16Stereoselective intermolecular rhodium-catalyzed C–H amination using sulfonimidamides.

cyclohexanone-derived silyl enolate 92(Scheme 17).70The E -geometry might be responsible for the unexpected formation of 94since products of a -amination such as 95have been isolated only from Z -enolates.71However,this hypothesis has been in part invalidated by the unsuccessful application of the reaction to cyclopentanone and -heptanone derivatives.Nevertheless,optimization of the reaction conditions by varying the chiral rhodium catalyst,the nitrene source,the solvent and the silyl group,has allowed compound 94to be isolated in 79%yield and 72%ee.More interestingly,Hashimoto managed to devise an elegant one-pot sequential rhodium-catalyzed 1,4-hydrosilylation/C–H amination from cyclohexenone that gives direct access to compound 96further transformed into Overman’s intermediate for the synthesis of (à)-pancracine (Scheme 18).

Amination via C–H activation

The development of numerous methodologies based on C–H activation for the selective functionalization of a C–H bond has received considerable attention within the last decade as testi?ed by the high number of recent reviews dedicated to this topic.10,72These processes have been applied to C–C,C–O or C–halogen bond formation but,paradoxically,no examples of C–H amination were inventoried until 2005.However,based on the early applications of iodine(III )reagents such PhI(OAc)2to palladium-catalyzed C–H oxygenation,73use

of the aza-analogous iminoiodanes for the related C–H

amination should have rapidly appeared as evident.This analogy did inspire Sanford et al.who described the PhI Q NTs-mediated amination of palladacycles formed,for example,by directed C–H activation of benzo[h ]quinoline (Scheme 19).74Nitrogen insertion into the Pd–C bond of 97might take place via a stepwise mechanism involving a discrete Pd(IV )–imido species or a concerted addition.Hydrolytic cleavage with HCl then releases the C–H-aminated product 99.However,this process remains stoichiometric in palladium(II )complexes,a major drawback that has not been circumvented so far.

The same deductive reasoning led Yu and Che to an identical conclusion,i.e.iminoiodanes are poorly active nitrogen donors in palladium-catalyzed C–H oxidation.Potassium persulfate K 2S 2O 8has thus been found to be a more adequate oxidant allowing Pd(OAc)2-catalyzed amination using sulfonamides,carbamates or even carboxamides.75Under these conditions,functionalization of either Csp 2-or Csp 3-H bonds occurs in very good yields in the 63–96%range.Excellent regioselectivity,at the ortho position in the case of aromatic substrates,or the b -hydrogen with alkyl substituents,is assured by catalyst pre-coordination to an appropriate tether,in most cases an O -methyl oxime (Scheme 20).Interestingly,contrary to the catalytic nitrene C–H insertion,the C–H functionalization has been shown here to take place preferentially at primary positions as a consequence of steric e?ects,a general trend of C–H activation-based reactions.The reaction also appears to be chemoselective since haloarenes prove to be inert and products arising from multiple aminations have not been isolated.

Iminoiodanes were ?nally found to be e?ective aminating agents in C–H activation in the presence of gold(III )catalysts.76Simple tri-,tetra-or penta-substituted arenes,though used in excess,react with AuCl 3to a?ord arylgold(III )intermediates,which are trapped by PhI Q NNs to give the C–H aminated products 107(Scheme 21).Strikingly,aromatic C–H bonds are preferentially functionalized over primary or secondary benzylic positions.

Intramolecular amination via C–H activation

The ?rst example of C–H activation for C–N bond formation was reported by Buchwald et al.in 200577and involved a combination of catalytic Pd(OAc)2and Cu(OAc)2as the stoichiometric co-oxidant.This has led to the

development

Scheme 17Allylic C–H amination of silyl enol ethers derived from

cyclohexanone.

Scheme 18Intermolecular C–H amination in total

synthesis.

Scheme 19Palladium-mediated C–H amination.

of a new protocol for the e?cient synthesis of carbazoles from biaryl acetamides a large variety of which can be easily prepared by application of Suzuki–Miyaura couplings (Scheme 22).Initial complexation of the catalyst to the nitrogen directs its regioselective addition on the other aromatic ring at the position ortho to the biaryl axis.A recent detailed study has demonstrated the capacity of DMSO to act as an alternative to Cu(OAc)2,thereby enhancing the scope of the reaction in terms of compatible substituents on both aromatic moieties.78This strategy provides a straightforward access to non-symmetrical carbazoles,as highlighted by the short syntheses (4to 6steps)of three naturally-occurring carbazoles in 68–79%yields.An even more signi?cant illustration of this e?cient protocol is the synthesis of 4-deoxycarbazomycin B 113via the application of two consecutive C–H activations to arene 111.79In parallel to these studies,the extension of this intramolecular C–H activation to N -(Ts)-hydrazones,80a N -(Ts)-enamines 80b and N -(Ts)-phenylacetamides 80c has allowed the design of a new route to,respectively,indazoles,indoles and oxindoles.Pd(0)/Pd(II )catalysis has been suggested as a possible mechanism.The C–N bond forming step,however,remains a matter of debate since the suggested intermediacy of a 6-membered palladacycle formed by ortho -palladation with concomitant release of acetic acid has been shown to be inconsistent with some experiments.

The design of an analogous Pd(II )/Pd(IV )process has been investigated with the aim of forcing the reductive elimination to occur under milder conditions,especially at a lower temperature than that needed in the above Pd(0)/Pd(II )

catalysis.This challenge has been successfully met by modi?cation of the oxidant and the nitrogen protecting group.Thus,replacing the former electron-withdrawing N -acetyl group by a more electron rich N -alkyl substituent allows intramolecular C–H amination at room temperature in the presence of PhI(OAc)2as the oxidant,the resulting carbazoles being obtained in very good yields ranging from 60%to 96%.81More fundamentally,complete chemoselectivity is observed in the case of aromatic substrates such as 114bearing an iodo likely to be engaged in coupling reactions (Scheme 23).The e?ciency of this carbazole synthesis is attested by its application to the preparation of a sensitive N -glycosyl derivative 117.In parallel,the use of N -methoxyamides of type 118has also been found practical leading in the presence of CuCl 2and AgOAc,to the corresponding lactams 119.82This procedure is con?ned to substrates displaying a gem -disubstitution adjacent to the carbonyl necessary for an e?cient catalysis,a limitation that has not prevented the extension of the reaction to a ,b -unsaturated amides.

Copper complexes have recently been shown to be suitable catalysts for similar intramolecular C–H activation,a reactivity that has been exploited for the formation of benzimidazoles 121from amidines 120(Scheme 24).83Although the scope is wider than that displayed by previously reported stoichio-metric oxidizing protocols,the reaction is still only con?ned to amidines derived from bulky ortho -substituted arylnitriles or trimethylacetonitrile.

As previously indicated,C–H activation is generally directed by the chelate e?ect,a strategy always applied in the intramolecular examples described so far.However,an alternative to this precoordination can be the targeting of activated positions,as extensively investigated in nitrene chemistry.Allylic substrates provide a textbook case of allowing selective catalytic intramolecular C–H activation–amination,a synthetic opportunity that has been rarely investigated until recently.84Fraunho?er and White have thus reported the use of Pd(OAc)2and a bis-sulfoxide ligand in the presence of phenyl-benzoquinone as the oxidant for the allylic

C–H

Scheme 21Gold-catalyzed C–H

amination.

Scheme 22Intramolecular Pd(0)/Pd(II )C–H activation for the synth-esis of

carbazoles.

Scheme 20Palladium-catalyzed C–H amination.

functionalization of terminal ole?ns.85Starting from various homoallylic N -tosylcarbamates 122,palladium-catalyzed intramolecular C–H amination leads to oxazolidinones,precursors of syn -1,2-amino alcohols.The reaction occurs with good yields and selectivities depending,however,on the substitution adjacent to the carbamoyl tether,a tertiary group such as an i -propyl giving the best compromise between reactivity and selectivity (Scheme 25).The reaction involves the formation of a p -allylpalladium intermediate observed by 1H NMR,following a C–H cleavage induced by the Pd(II )–bis-sulfoxide complex.This ligand,previously described for analogous C–H oxidation,86is crucial for the chemo-selectivity since it does not promote the possible competitive aminopalladation step.The use of an N -tosylcarbamate as the nucleophile has also proven optimal:its weak Lewis basicity prevents any interaction with the catalyst and the N–H acidity allows its deprotonation by the acetate counterion of the Pd(II )complex.

Intermolecular amination via C–H activation

Intermolecular allylic C–H activation–amination has been studied by Nicholas and Srivastava since the early 90s.They have demonstrated the ability of molybdenum(VI ),iron(II ,III )and copper(I )complexes to catalyze C–H amination with

arylhydroxylamines as the nucleophiles.87The addition of

nitrogen takes place regioselectively at the less substituted carbon of the starting alkene leading to N -aryl-N -allylamines in modest yields although the ole?ns must be used in excess,a low reactivity that limits the synthetic potential of this reaction.More promising appears to be the recent study of Reed and White who,inspired by the aforementioned intramolecular protocol,developed a catalytic heterobimetallic intermolecular version.It was then demonstrated that a combination of Pd(OAc)2–bis-sulfoxide and chromium(III )complex e?ciently promotes the transformation of various terminal ole?ns used in stoichiometric amounts into linear (E )-allylic amines with excellent regio-and stereoselectivities (linear :branched amines:420:1;(E ):(Z )ole?ns:420:1,Scheme 26).88The reaction appears compatible with a wide range of functions,therefore o?ering unprecedented synthetic opportunities as highlighted by a short preparation of (+)-deoxynegamycin.It can also be applied to the preparation of 15N-labeled compounds.In terms of regioselectivity,this procedure complements the former intramolecular version,wherein the internal nucleophilic delivery directs the substitution to the secondary allylic position.The p -allylpalladium intermediate,once again generated after Pd(II )–bis-sulfoxide-induced C–H cleavage,here undergoes amination at the primary site,a ?nal step promoted by the Cr(III )salen complex in conjunction

with

Scheme 24Intramolecular copper-catalyzed C–H

activation.

Scheme 25Intramolecular palladium-catalyzed allylic C–H

activation.

Scheme 26Intermolecular heterobimetallic-catalyzed allylic C–H

amination.

Scheme 23Intramolecular Pd(II )/Pd(IV )C–H activation.

benzoquinone.Independently,Liu et al.have described an analogous intermolecular allylic C–H amination that displays the same regioselectivity and tolerance towards various functional groups.This involves the use of Pd(OAc)2and sodium acetate under a dioxygen atmosphere in the presence of maleic anhydride,which facilitates nucleophilic amination of the p-allylpalladium intermediate,as previously demonstrated with the chromium catalyst and benzoquinone(Scheme27).89 However,the overall process displays lower e?ciency since good yields are assured only with3equivalents of alkene or the use of20mol%of Pd(II)catalyst.Homo-and bishomo-allylimides are,moreover,sometimes formed as by-products in signi?cant quantities.

Finally,as in the case of intramolecular C–H activation, copper complexes have also been shown to catalyze inter-molecular C–H aminations.These generally involve a copper(II) catalyst(chloride or acetate)under a dioxygen atmosphere, while the regioselectivity of the process relies either on the precomplexation of the metal90or the functionalization of activated positions found in terminal alkynes91or azoles.92 Conclusions

While the?eld of C–H amination was a sort of no man’s land at the beginning of this century,it has received increasing attention with several breakthroughs being made within the last few years.Intramolecular C–H amination via catalytic nitrene insertion is now a well-established reaction with outstanding applications reported in complex natural products total synthesis.Of striking importance is the high degree of regio-and chemoselective control achieved in these reactions,the internal delivery of the nitrene being assured by di?erent classes of tethers.The recent emergence of analogous intramolecular C–H activation–amination protocols,which display similar levels of e?ciency and selectivity,should rapidly lead to a growing number of applications such that intramolecular C–H amination should soon join the pantheon of classic organic reactions.

More recent and impressive are the improvements made within the last three years in the?eld of the related inter-molecular transformation.Devising an e?cient process in this context required facing the challenges of reactivity,chemo-, regio-and stereoselectivity.17f These hurdles have nevertheless been overcome by the careful design of ligands and reagents. Highly e?cient methodologies are now available to target a selective C–H bond in benzylic and allylic substrates as well as in simple cyclic alkanes used in stoichiometric amounts.This can be envisaged by either C–H insertion or C–H activation, each approach leading to excellent but complementary regioselectivities.While primary positions are selectively functionalized in the case of C–H activation-based amination as a consequence of steric e?ects,secondary sites are generally favored in C–H insertions,a compromise between electronic and steric factors.Electron-rich tertiary C–H bonds still remain accessible using nitrene methodology,though with lower e?ciency.Equally impressive is the chemoselectivity associated with these processes that a?ord in all cases mono-aminated products and negligible or no by-products such as aziridines in the case of allylic C–H https://www.docsj.com/doc/a713665678.html,st but not least,even C–H functionalization with nearly complete stereo-selectivity has been achieved through the use of chiral nitrene precursors.All these signi?cant results should now be validated by their applications to selective intermolecular C–H amination of complex compounds by analogy with a recent work devoted to catalytic C–H oxidation.93

Finally,the nitrene chemistry has re-emerged with the combined use of transition metal catalysts and iodine(III) oxidants.Further investigations will undoubtedly lead to the discovery of new transformations as highlighted by the recently published amidation of aldehyde.94However,despite the recent characterization of copper–nitrene complexes,much work remains to be done in order to draw a clear picture of the overall mechanism,which,so far,has mainly been based on indirect evidence.This should help to design more atom-economical but equally e?cient and selective aminating agents.Ultimately,these studies should allow organic chemists to?nally attain one of their holy grails,i.e.the selective functionalization of simple alkanes. Acknowledgements

We would like to warmly thank all the co-workers whose names are listed in our references below,and the Institut de Chimie des Substances Naturelles for?nancial support and fellowships(F.C.).Supports and sponsorships concerted by COST Action D40‘‘Innovative Catalysis:New Processes and Selectivities’’and ANR-08-BLAN-0013-01are also kindly acknowledged.

Notes and references

1Comprehensive Natural Products Chemistry,ed.D.H.R.Barton, K.Nakanishi and O.Meth-Cohn,Elsevier,Oxford,1999,vol.4. 2(a)R.Hili and A.K.Yudin,Nat.Chem.Biol.,2006,6,284;

(b)M.Feher and J.M.Schmidt,https://www.docsj.com/doc/a713665678.html,put.Sci.,2003,

43,218;(c)T.Henkel,R.M.Brunne,H.Mu ller and F.Reichel, Angew.Chem.,Int.Ed.,1999,38,643.

3(a)N.K.Boaen and M.A.Hillmyer,Chem.Soc.Rev.,2005,34, 267;(b)S.Banerjee,T.Hemraj-Benny and S.S.Wong,Adv.

Mater.,2005,17,17.

4Comprehensive Organic Synthesis,ed.B.M.Trost and I.Fleming, Pergamon Press,Oxford,1991,vol.6.

5(a)J. F.Hartwig,Nature,2008,455,314;(b)Amino Group Chemistry From Synthesis to the Life Sciences,ed. A.Ricci, Wiley-VCH,Weinheim,2008;(c)Modern Amination Methods, ed. A.Ricci,Wiley-VCH,Weinheim,2000;(d)M.Kienle, S.R.Dubbaka,K.Brade and P.Knochel,https://www.docsj.com/doc/a713665678.html,.Chem., 2007,4166.

6For recent reviews,see:(a)D.S.Surry and S.L.Buchwald,Angew.

Chem.,Int.Ed.,2008,47,6338;(b)J.F.Hartwig,Acc.Chem.Res., 2008,41,1534.

7T.E.Mu ller,K.C.Hultzsch,M.Yus,F.Foubelo and M.Tada, Chem.Rev.,2008,108,3795.

8R.Marcia de Figueiredo,Angew.Chem.,Int.Ed.,2009,48,

1190. Scheme27Intermolecular palladium-catalyzed allylic C–H amination.

9(a)Y.Takemoto and H.Miyabe,Comprehensive Organometallic Chemistry III,ed.R.H.Crabtree and D.M.P.Mingos,Elsevier, Oxford,2007,vol.10,p.695;(b)M.Johannsen and K.A.Jorgensen,Chem.Rev.,1998,98,1689.

10(a)R.G.Bergman,Nature,2007,446,391;(b)K.Godula and

D.Sames,Science,2006,312,67;(c)Handbook of C–H Transforma-

tions,ed.G.Dyker,Wiley-VCH,Weinheim,2005;(d)F.Kakiuchi and N.Chatani,Adv.Synth.Catal.,2003,345,1077;(e)V.Ritleng,

C.Sirlin and M.Pfe?er,Chem.Rev.,2002,102,1731;

(f)https://www.docsj.com/doc/a713665678.html,binger and J.E.Bercaw,Nature,2002,417,507.

11H.Kwart and A.A.Kahn,J.Am.Chem.Soc.,1967,89,1951. 12D.S.Breslow and M.F.Sloan,Tetrahedron Lett.,1968,5349. 13D.Carr,T.P.Seden and R.W.Turner,Tetrahedron Lett.,1969, 477.

14(a)R.Breslow and S.H.Gellman,J.Chem.Soc.,https://www.docsj.com/doc/a713665678.html,mun., 1982,1400;(b)R.Breslow and S.H.Gellman,J.Am.Chem.Soc., 1983,105,6728.

15J.-P.Mahy,G.Bedi,P.Battioni and D.Mansuy,New J.Chem., 1989,13,651.

16A.Hinman and J.Du Bois,J.Am.Chem.Soc.,2003,125,11510. 17(a)P.Dauban and R.H.Dodd,in Amino Group Chemistry,From Synthesis to the Life Sciences,ed.A.Ricci,Wiley-VCH,Weinheim, 2008,p.55;(b)H.M.L.Davies and J.R.Manning,Nature,2008, 451,417;(c)M.M.D?az-Requejo and P.J.Pe rez,Chem.Rev., 2008,108,3379;(d)H.M.L.Davies and X.Dai,in Comprehensive Organometallic Chemistry III,ed.R.H.Crabtree and D.M.P.

Mingos,Elsevier,Oxford,2007,p.167;(e)https://www.docsj.com/doc/a713665678.html,pain and S.Toumieux,Targets in Heterocyclic Systems,ed.O.A.Attanasi and D.Spinelli,Royal Society of Chemistry,Cambridge,2007,vol.

11,p.344;(f)A.R.Dick and M.S.Sanford,Tetrahedron,2006,62, 2439;(g)H.M.L.Davies,Angew.Chem.,Int.Ed.,2006,45,6422;

(h)H.M.L.Davies and M.S.Long,Angew.Chem.,Int.Ed.,2005,

44,3518;(i)C.G.Espino and J.Du Bois,in Modern Rhodium-Catalyzed Organic Reactions,ed.P. A.Evans,Wiley-VCH, Weinheim,2005,p.379;(j)J.A.Halfen,https://www.docsj.com/doc/a713665678.html,.Chem.,2005, 9,657;(k)J.Du Bois,Chemtracts:Org.Chem.,2005,18,1;

(l)P.Mu ller and C.Fruit,Chem.Rev.,2003,103,2905;

(m)P.Dauban and R.H.Dodd,Synlett,2003,1571.

18R.H.Crabtree,J.Chem.Soc.,Dalton Trans.,2001,2437.

19C.G.Espino and J.Du Bois,Angew.Chem.,Int.Ed.,2001,40, 598.

20(a)C.G.Espino,P.M.Wehn,J.Chow and J.Du Bois,J.Am.

Chem.Soc.,2001,123,6935;(b)J.J.Fleming,K.W.Fiori and J.Du Bois,J.Am.Chem.Soc.,2003,125,2028;(c)K.W.Fiori, J.J.Fleming and J.Du Bois,Angew.Chem.,Int.Ed.,2004,43, 4349;(d)K.W.Fiori,C.G.Espino,B.H.Brodsky and J.Du Bois, Tetrahedron,2009,65,3042.

21X.Lin, C.Zhao, C.-M.Che,Z.Ke and D.L.Phillips, Chem.–Asian J.,2007,2,1101.

22K.A.Parker and W.Chang,Org.Lett.,2005,7,1785.

23C.J.Hayes,P.W.Beavis and L.A.Humphries,https://www.docsj.com/doc/a713665678.html,mun., 2006,4501.

24For reviews devoted to ligand e?ects on chemoselectivity,see:

(a)M.P.Doyle and T.Ren,in Progress in Inorganic Chemistry,

ed.K.Karlin,Wiley,New York,2001,vol.49,p.113;

(b)A.Padwa and D.J.Austin,Angew.Chem.,Int.Ed.Engl.,

1994,33,1797.

25(a)C.G.Espino,K.W.Fiori,M.Kim and J.Du Bois,J.Am.

Chem.Soc.,2004,126,15378;(b)M.Kim,J.V.Mulcahy,

C.G.Espino and J.Du Bois,Org.Lett.,2006,8,1073;

(c)T.Kurokawa,M.Kim and J.Du Bois,Angew.Chem.,Int.

Ed.,2009,48,2777.

26D.E.Olson and J.Du Bois,J.Am.Chem.Soc.,2008,130,11248. 27(a)C.Fruit and P.Mu ller,Helv.Chim.Acta,2004,87,1607;

(b)M.Yamawaki,S.Kitagaki,M.Anada and S.Hashimoto,

Heterocycles,2006,69,527.

28D.N.Zalatan and J.Du Bois,J.Am.Chem.Soc.,2008,130,9220. 29(a)J.-L.Liang,S.-X.Yuan,J.-S.Huang,W.-Y.Yu and

C.-M.Che,Angew.Chem.,Int.Ed.,2002,41,3465;

(b)J.-L.Liang,S.-X.Yuan,J.-S.Huang and C.-M.Che,https://www.docsj.com/doc/a713665678.html,.

Chem.,2004,69,3610.

30(a)J.Zhang,P.W.H.Chan and C.-M.Che,Tetrahedron Lett., 2005,46,5403;(b)https://www.docsj.com/doc/a713665678.html,czek,N.Boudet and S.Blakey,Angew.

Chem.,Int.Ed.,2008,47,6825.31(a)H.Lebel,K.Huard and S.Lectard,J.Am.Chem.Soc.,2005, 127,14198;(b)K.Huard and H.Lebel,Chem.–Eur.J.,2008,14, 6222.

32R.P.Reddy and H.M.L.Davies,Org.Lett.,2006,8,5013.

33(a)Nitrenes,ed.W.Lwowski,Interscience,New York,1970;

(b) C.J.Moody,in Comprehensive Organic Synthesis,

ed.B.M.Trost and I.Fleming,Pergamon Press,Oxford,1991, vol.6,p.21.

34(a)T.Katsuki,Chem.Lett.,2005,1304;(b)S.Cenini,E.Gallo,

A.Caselli,F.Ragaini,S.Fantauzzi and C.Piangiolino,Coord.

Chem.Rev.,2006,250,1234.

35(a)B.J.Stokes,H.Dong,B.E.Leslie,A.L.Pumphrey and T.G.Driver,J.Am.Chem.Soc.,2007,129,7500;(b)M.Shen,

B.E.Leslie and T.G.Driver,Angew.Chem.,Int.Ed.,2008,47,

5056;(c)H.Dong,M.Shen,J. E.Redford, B.J.Stokes,

A.L.Pumphrey and T.G.Driver,Org.Lett.,2007,9,5191.

36F.Ragaini, A.Penoni, E.Gallo,S.Tollari, C.Li Gotti, https://www.docsj.com/doc/a713665678.html,padula,E.Mangioni and S.Cenini,Chem.–Eur.J.,2003, 9,249.

37J.V.Ruppel,R.M.Kamble and X.P.Zhang,Org.Lett.,2007,9, 4889.

38S.V.Narina,T.S.Kumar,S.George and A.Sudalai,Tetrahedron Lett.,2007,48,65.

39(a)T.Yakura,Y.Yoshimoto,C.Ishida and S.Mabuchi,Tetra-hedron,2007,63,4429;(b)T.Yakura,Y.Yoshimoto and C.Ishida, Chem.Pharm.Bull.,2007,55,1385;(c)T.Yakura,S.Sato and Y.Yoshimoto,Chem.Pharm.Bull.,2007,55,1284.

40S.Wang and D.Romo,Angew.Chem.,Int.Ed.,2008,47,1284. 41(a)J.V.Mulcahy and J.Du Bois,J.Am.Chem.Soc.,2008,130, 12630;for a related oxyamination of indoles,see:;(b)A.Padwa,

A.C.Flick,C.A.Leverett and T.Stengel,https://www.docsj.com/doc/a713665678.html,.Chem.,2004,69,

6377.

42Y.Liu,W.Xiao,M.-K.Wong and C.-M.Che,Org.Lett.,2007,9, 4107.

43(a)J.J.Fleming and J.Du Bois,J.Am.Chem.Soc.,2006,128, 3926;(b)J.J.Fleming,M.D.McReynolds and J.Du Bois,J.Am.

Chem.Soc.,2007,129,9964.

44R.M.Conrad and J.Du Bois,Org.Lett.,2007,9,5465.

45(a)R.E.Mele ndez and W.D.Lubell,Tetrahedron,2003,59,2581;

(b)F.J.Dura n,L.Leman,A.A.Ghini,G.Burton,P.Dauban and

R.H.Dodd,Org.Lett.,2002,4,2481.

46(a)S.Toumieux,https://www.docsj.com/doc/a713665678.html,pain and O.R.Martin,https://www.docsj.com/doc/a713665678.html,.Chem., 2008,73,2155;(b)M.S.T.Morin,S.Toumieux,https://www.docsj.com/doc/a713665678.html,pain, S.Peyrat and J.Kalinowska-Tluscik,Tetrahedron Lett.,2007,48, 8531;(c)S.Toumieux,https://www.docsj.com/doc/a713665678.html,pain,O.R.Martin and M.Selkti, Org.Lett.,2006,8,4493.

47For a rare example of molecular recognition in selective oxidation of C–H bonds,see:S.Das,C.D.Incarvito,R.H.Crabtree and

G.W.Brudvig,Science,2006,312,1941.

48(a)X.-Q.Yu,J.-S.Huang,X.-G.Zhou and C.-M.Che,Org.Lett., 2000,2,2233;(b)S.-M.Au,J.-S.Huang,C.-M.Che and W.-Y.Yu, https://www.docsj.com/doc/a713665678.html,.Chem.,2000,65,7858;(c)J.-L.Liang,J.-S.Huang, X.-Q.Yu,N.Zhu and C.-M.Che,Chem.–Eur.J.,2002,8,1563;

(d)S.-M.Au,J.-S.Huang,W.-Y.Yu,W.-H.Fung and C.-M.Che,

J.Am.Chem.Soc.,1999,121,9120.

49R.M.Moriarty,C.J.Chany II,R.K.Vaid,O.Prakash and S.M.Tuladhar,https://www.docsj.com/doc/a713665678.html,.Chem.,1993,58,2478,and references therein.

50J.D.Harden,J.V.Ruppel,G.-Y.Gao and X.P.Zhang,Chem.

Commun.,2007,4644.

51B.Kalita,https://www.docsj.com/doc/a713665678.html,mar and K.M.Nicholas,https://www.docsj.com/doc/a713665678.html,mun., 2008,4291.

52Z.Wang,Y.Zhang,H.Fu,Y.Jiang and Y.Zhao,Org.Lett.,2008, 10,1863.

53(a)Y.Cui and C.He,Angew.Chem.,Int.Ed.,2004,43,4210;

(b)Z.Li,D.A.Capretto,R.Rahaman and C.He,Angew.Chem.,

Int.Ed.,2007,46,5184.

54B.P.Go mez-Emeterio,J.Urbano,M.M.D?az-Requejo and P.J.Pe rez,Organometallics,2008,27,4126.

55M.R.Fructos,S.Tro?menko,M.M.D?az-Requejo and P.J.Pe rez,J.Am.Chem.Soc.,2006,128,11784.

56D.P.Albone,S.Challenger, A.M.Derrick,S.M.Fillery, J.L.Irwin, C.M.Parsons,H.Takada,P. C.Taylor and

D.J.Wilson,Org.Biomol.Chem.,2005,3,10.

57R.Bhuyan and K.M.Nicholas,Org.Lett.,2007,9,3957.

58L.He,J.Yu,J.Zhang and X.-Q.Yu,Org.Lett.,2007,9,227. 59(a)Y.Kohmura,K.-I.Kawasaki and T.Katsuki,Synlett,1997, 1456;(b)J.S.Clark and C.Roche,https://www.docsj.com/doc/a713665678.html,mun.,2005,5175;

(c)G.Pelletier and D. A.Powell,Org.Lett.,2006,8,6031;

(d)Y.Zhang,H.Fu,Y.Jiang and Y.Zhao,Org.Lett.,2007,9,

3813;(e)X.Liu,Y.Zhang,L.Wang,H.Fu,Y.Jiang and Y.Zhao, https://www.docsj.com/doc/a713665678.html,.Chem.,2008,73,6207.

60(a)Y.M.Badiei, A.Krishnaswamy,M.M.Melzer and T.H.Warren,J.Am.Chem.Soc.,2006,128,15056;

(b)Y.M.Badiei, A.Dinescu,X.Dai,R.M.Palomino,

F.W.Heinemann,T.R.Cundari and T.H.Warren,Angew.

Chem.,Int.Ed.,2008,47,9961;(c)T.R.Cundari,A.Dinescu and

A.B.Kazi,Inorg.Chem.,2008,47,10067.

61I.Na geli,C.Baud,G.Bernardinelli,Y.Jacquier,M.Moran and P.Mu ller,Helv.Chim.Acta,1997,80,1087.

62M.Yamawaki,H.Tsutsui,S.Kitagaki,M.Anada and S.Hashimoto,Tetrahedron Lett.,2002,43,9561.

63C.Fruit and P.Mu ller,Tetrahedron:Asymmetry,2004,15,1019. 64K.W.Fiori and J.Du Bois,J.Am.Chem.Soc.,2007,129,562. 65(a)P.Di Chenna,F.Robert-Peillard,P.Dauban and R.H.Dodd, Org.Lett.,2004,6,4503;(b) C.Fruit, F.Robert-Peillard,

G.Bernardinelli,P.Mu ller,R.H.Dodd and P.Dauban,

Tetrahedron:Asymmetry,2005,16,3484.

66C.Liang,F.Robert-Peillard,C.Fruit,P.Mu ller,R.H.Dodd and P.Dauban,Angew.Chem.,Int.Ed.,2006,45,4641.

67C.Liang,F.Collet,F.Robert-Peillard,P.Mu ller,R.H.Dodd and P.Dauban,J.Am.Chem.Soc.,2008,130,343.

68H.Lebel and K.Huard,Org.Lett.,2007,9,639.

69J.Yang,R.Weinberg and R.Breslow,https://www.docsj.com/doc/a713665678.html,mun.,2000, 531.

70M.Anada,M.Tanaka,N.Shimada,H.Nambu,M.Yamawaki and S.Hashimoto,Tetrahedron,2009,65,3069.

71(a)M.Anada,M.Tanaka,T.Washio,M.Yamawaki,T.Abe and S.Hashimoto,Org.Lett.,2007,9,4559;(b)M.Tanaka, Y.Kurosaki,T.Washio,M.Anada and S.Hashimoto, Tetrahedron Lett.,2007,48,8799.

72(a)J.C.Lewis,R.G.Bergman and J.A.Ellman,Acc.Chem.Res., 2008,41,1013;(b)Y.J.Park,J.-W.Park and C.-H.Jun,Acc.

Chem.Res.,2008,41,222;(c)F.Kakiuchi and T.Kochi,Synthesis, 2008,3013;(d)B.-J.Li,S.-D.Yang and Z.-J.Shi,Synlett,2008, 949;(e)L.Ackermann,https://www.docsj.com/doc/a713665678.html,anomet.Chem.,2007,24,35;

(f)D.Kalyani and M.S.Sanford,https://www.docsj.com/doc/a713665678.html,anomet.Chem.,2007,

24,85;(g)T.Satoh and M.Miura,Chem.Lett.,2007,36,200;

(h)D.Alberico,M.E.Scott and https://www.docsj.com/doc/a713665678.html,utens,Chem.Rev.,2007,

107,174;(i)C.I.Herrerias,X.Yao,Z.Li and C.-J.Li,Chem.Rev., 2007,107,2546;(j)K.R.Campos,Chem.Soc.Rev.,2007,36,1069;

(k)I.V.Seregin and V.Gevorgyan,Chem.Soc.Rev.,2007,36, 1173;(l)J.-Q.Yu,R.Giri and X.Chen,Org.Biomol.Chem.,2006, 4,4041;(m)L.A.Goj and T.B.Gunnoe,https://www.docsj.com/doc/a713665678.html,.Chem.,2005, 9,671.

73(a)T.Yoneyama and R.H.Crabtree,J.Mol.Catal.A:Chem., 1996,108,35;(b)A.R.Dick,K.L.Hull and M.S.Sanford,J.Am.

Chem.Soc.,2004,126,2300.74A.R.Dick,M.S.Remy,J.W.Kampf and M.S.Sanford, Organometallics,2007,26,1365.

75H.-Y.Thu,W.-Y.Yu and C.-M.Che,J.Am.Chem.Soc.,2006, 128,9048.

76Z.Li,D.A.Capretto,R.O.Rahaman and C.He,J.Am.Chem.

Soc.,2007,129,12058.

77W.C.P.Tsang,N.Zheng and S.L.Buchwald,J.Am.Chem.Soc., 2005,127,14560.

78W. C.P.Tsang,R.H.Munday,G.Brasche,N.Zheng and S.L.Buchwald,https://www.docsj.com/doc/a713665678.html,.Chem.,2008,73,7603.

79B.-J.Li,S.-L.Tian,Z.Fang and Z.-J.Shi,Angew.Chem.,Int.Ed., 2008,47,1115.

80(a)K.Inamoto,T.Saito,M.Katsuno,T.Sakamoto and K.Hiroya,Org.Lett.,2007,9,2931;(b)K.Inamoto,T.Saito, K.Hiroya and T.Doi,Synlett,2008,20,3157;(c)T.Miura,Y.Ito and M.Murakami,Chem.Lett.,2009,38,328.

81J.A.Jordan-Hore,C.C.C.Johansson,M.Gulias,E.M.Beck and M.J.Gaunt,J.Am.Chem.Soc.,2008,130,16184.

82M.Wasa and J.-Q.Yu,J.Am.Chem.Soc.,2008,130,14058.

83G.Brasche and S.L.Buchwald,Angew.Chem.,Int.Ed.,2008,47, 1932.

84For earlier examples of catalytic intramolecular allylic C–H ami-nation,see:(a)M.Ro nn,J.-E.Ba ckvall and P.G.Andersson, Tetrahedron Lett.,1995,36,7749;(b)R. https://www.docsj.com/doc/a713665678.html,rock, T.R.Hightower,L.A.Hasvold and K.P.Peterson,https://www.docsj.com/doc/a713665678.html,.

Chem.,1996,3584.For studies involving a stoichiometric amount of palladium catalyst,see:;(c)C.H.Heathcock,J.A.Sta?ord and

D.L.Clark,https://www.docsj.com/doc/a713665678.html,.Chem.,1992,57,2575;(d)P.A.Van der

Schaaf,J.-P.Sutter,M.Grellier,G.P.M.van Mier,A.L.Spek,

G.van Koten and M.Pfe?er,J.Am.Chem.Soc.,1994,116,5134. 85K.J.Fraunho?er and M.C.White,J.Am.Chem.Soc.,2007,129, 7274.

86(a)M.S.Chen and M.C.White,J.Am.Chem.Soc.,2004,126, 1346;(b)K.J.Fraunho?er,N.Prabagaran,L. E.Sirois and M.C.White,J.Am.Chem.Soc.,2006,128,9032.

87(a)R.S.Srivastava and K.M.Nicholas,https://www.docsj.com/doc/a713665678.html,.Chem.,1994,59, 5365;(b)R.S.Srivastava and K.M.Nicholas,J.Am.Chem.Soc., 1997,119,3302;(c)R.S.Srivastava,N.R.Tarver and K.M.Nicholas,J.Am.Chem.Soc.,2007,129,15250.

88S.A.Reed and M.C.White,J.Am.Chem.Soc.,2008,130,3316. 89G.Liu,G.Yin and L.Wu,Angew.Chem.,Int.Ed.,2008,47,4733. 90(a)X.Chen,X.-S.Hao,C.E.Goodhue and J.-Q.Yu,J.Am.

Chem.Soc.,2006,128,6790;for a similar reaction involving stoichiometric amount of copper(II)acetate,see:;(b)T.Uemura, S.Imoto and N.Chatani,Chem.Lett.,2006,35,842.

91T.Hamada,X.Ye and S.S.Stahl,J.Am.Chem.Soc.,2008,130, 833.

92D.Monguchi,T.Fujiwara,H.Furukawa and A.Mori,Org.Lett., 2009,11,1607.

93M.S.Chen and M.C.White,Science,2007,318,783.

94(a)J.Chan,K.D.Baucom and J.A.Murry,J.Am.Chem.Soc., 2007,129,14106;(b)J.W.W.Chang and P.W.H.Chan,Angew.

Chem.,Int.Ed.,2008,47,1138.

(完整word版)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。衍生自氨的亚胺倾向于不稳定 - 即使用水也经常迅速水解产生羰基化合物，并且通常易于聚合。 三：苯基丙酮与阮内镍的高压还原胺化工艺步骤：

苯基丙酮还原胺化产物的酒石酸拆分研究

:还原胺化反应的定义: 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。将羰基跟胺反应生成亚胺（席夫碱），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。 还原胺化反应结束，后处理后我们得到的是外消体DL型甲 基苯丙胺。而还原胺化得到的DL型甲基苯丙胺药效则要差 很多，药效的差异是因为一个叫做“手性”的化学现象，而与纯度无关。正如人的左右手是各自的镜像一样，虽然外形一样，但其实是相反的，两种有机化合物也能以相互的镜像形式存在。由于甲基苯丙胺有一个手性中心，它有两种不同的称为“对映异构体”的镜像形式，也就是D型与L型，其 中D型与L型各占一半。（按取代基的先后顺序来分是R型和S型，按与平面偏振光的作用来分是D型和L型，L是左旋，用-标识，D为右旋，用+标识，一般使用D型作为拆分剂）。因为平面的苯基丙酮一亚甲胺没有手性，因而氢加成在平面亚胺键两侧发生的几率是相同的。对映异构体一般有着

完全不同的生物效应，虽然它们看上去是一样的，在分子含量、结构以及外观上并没有区别，可以说完全一样，只是在紫外线的照射下，反射回来的光偏向不一样，往左偏的是 “ L型甲基苯丙胺”，往右偏的是“ D型甲基苯丙胺”。但它们的作用形式并不总是一样的，主要在药效上不同。其中D 型甲基苯丙胺有典型的兴奋作用，而L型甲基苯丙胺的兴奋 作用很弱，D型甲基苯丙胺对人体大脑中枢神经的兴奋作用是L型甲基苯丙胺的20倍。而甲基苯丙胺的对映异构体之间相互转化不是很容易，因为它手性中心上没有酸性氢。 二：酒石酸的性质与用途介绍： 中文名：酒石酸 夕卜文名:tartaric acid 分子质量：150.09 CAS号:87-69-4 , 526-83-0 简称:TA 状态:单斜晶体(无水) 英文别名：2,3-Dihydroxybutanedioic acid 熔点：171-174 密度：1.7598 (20) 折光率：1.4955 溶解度：溶于水、丙酮、乙醇 存在：酒石酸在水中溶解度：右旋酒石酸139，左旋酒石酸139，内消旋酒石酸125,外消旋酒石酸20.6。

胺的合成反应综述

Studies in Synthetic Chemistry 合成化学研究, 2016, 4(2), 11-18 Published Online June 2016 in Hans. https://www.docsj.com/doc/a713665678.html,/journal/ssc https://www.docsj.com/doc/a713665678.html,/10.12677/ssc.2016.42002 文章引用: 何永富, 李荣疆. 胺的合成反应综述[J]. 合成化学研究, 2016, 4(2): 11-18. The Summary of the Synthesis of Amines Yongfu He, Rongjiang Li Hangzhou Yuanchang Pharmaceutical Sci-Tech Co., Ltd., Hangzhou Zhejiang Received: Sep. 30th , 2016; accepted: Oct. 16th , 2016; published: Oct. 19th , 2016 Copyright ? 2016 by authors and Hans Publishers Inc. This work is licensed under the Creative Commons Attribution International License (CC BY). https://www.docsj.com/doc/a713665678.html,/licenses/by/4.0/ Abstract Amines, as a class of very effective drug functional groups, exist on most pharmaceutical struc-tures. In this paper, we summarize the main methods for the synthesis of existing amines, and ex-plore the methods for the synthesis of novel amines. Keywords Amine, Amino, Synthesis of Amines 胺的合成反应综述 何永富，李荣疆 杭州源昶医药科技有限公司，浙江 杭州 收稿日期：2016年9月30日；录用日期：2016年10月16日；发布日期：2016年10月19日 摘 要 胺作为一类非常有效的药物官能团，存在于大多数药物结构之上。本文总结现有胺的合成的主要方法，以及探索寻找新的胺的合成方法。 Open Access

还原胺化反应的新进展

2007年第27卷有机化学V ol. 27, 2007第1期, 1～7 Chinese Journal of Organic Chemistry No. 1, 1～7 * E-mail: wangdq@https://www.docsj.com/doc/a713665678.html, Received December 8, 2005; revised March 20, 2006; accepted May 8, 2006.

2 有 机 化 学 V ol. 27, 2007 合成中得到广泛应用[2]. 最近Blechert 等[3]报道了多官能团化合物1在Pd/C 催化氢化条件下“一锅”完成双键还原、酮羰基还原胺化、醛的脱保护、醛的还原胺化、苄氧羰基的脱除5步反应形成双环哌啶并吡咯啉化合物2 (Eq. 1). 除了Pd 以外, 其它金属如Ni, Pt 等也被用作氢化胺化催化剂. Nugent 等[4]报道了在烷氧钛的存在下, 不对称烷基酮与(R )-1-甲基苄胺(MBA)反应, Raney-Ni 催化氢化产生立体选择性非常高的二级胺3, 然后Pd/C 催化氢解给出收率和旋光性比较好的一级胺4 (71%～78%收率, 72%～98% ee ) (Scheme 1). 同样如果烷基酮与 (S )-MBA 反应、氢解可以得到与3和4相反构型的胺. 该方法尽管从酮开始需要两步反应产生手性一级胺, 但试剂价廉易得, 有利于规模化生产 . Scheme 1 1.2 金属络合物催化还原胺化 金属络合物在催化氢化方面具有优异的催化活性, 而且比仅用金属催化氢化具有更好的选择性. Beller 等[5]报道了0.05 mol%的[Rh(cod)Cl]2与TPPTS (tris so-dium salt of meta trisulfonated triphenylphosphine)形成络合物催化各种醛与氨的还原胺化, 得到高收率的胺化产物(最高97%) (Eq. 2). Rh 络合物易溶于水, 反应可在水溶液中进行 . Angelovski 等[6]应用0.5 mol%的[Rh(acac)(CO)2]催化氢化大环二醛与二胺形成大环二胺, 收率57%～76%, 而用其它还原胺化试剂[NaBH 3CN, NaB(AcO)3H]只得到 不超过30%收率的产物. Rh 络合物在参与关环过程中具有更好的模板效应. 2005年, Ohta [7]报道了以离子液体咪唑盐7为反应介质, 2 mol% [Ir(cod)2]BF 4进行的直接还原胺化, 不需任何配体的参与, 往离子液体中通入一定压力氢气, 获得收率79%～99%的二级胺(Eq. 3). 离子液体的阴离子部分对反应影响很大, 以[Bmim]BF 4为介质时收率最好. 氢气压力增大、温度升高有利于反应速率和收率的提高 . 天然含有胺基的化合物(吗啡、麻黄碱、氨基酸等)往往都是光活性的, 手性胺基的获得有着更重要的意义, 也是该领域研究的热点. 由醛(酮)直接或间接还原胺化为立体专一异构体是获得手性胺基化合物的重要途径. 目前已报道的是手性过渡金属络合物不对称催化还原亚胺[8], 其中以Ir, Rh 和Ru 与手性配体形成的络合物进行的不对称还原胺化较为常见. 2004年Andersson [9]报道了Ir 的络合物催化亚胺还原胺化反应(Eq. 4). 由酮与胺反应, 经过亚胺8, 然后被膦-噁唑啉与铱的络合物10进行催化氢化, 可得R 型为主的手性胺9 . Kadyrov 等[10]报道了同样的反应, 以[(R )-tol-binap]- RuCl 2为催化剂对芳香酮的还原胺化, 得到84% ee 的R -异构体, 而对脂肪酮的反应, 对映选择性一般低于30%. 由酮与胺形成亚胺, 不需分离直接进行还原是更简单实用的方法, 然而成功的报道为数不多[11]. 2003年, Zhang 等[12]报道了在Ti(OPr-i )4存在下, Ir-f-Binaphane (14)催化氢化各种芳香酮与对甲氧苯胺的还原胺化, 取得收率和对映选择性都非常好的结果(最低93%收率, 最高96% ee ), 其反应过程见Scheme 2. 首先在Lewis 酸

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)，

苯基丙酮还原胺化铝汞齐法还原工艺

方法1：甲胺醇氨化： 众所周知，用活化的铝和氨衍生物还原羟基酮或多羰基化合物导致形成相应的氨基醇。这个反应是有利的，因为羟基酮和聚羰基易于形成相对稳定的亚胺。本发明涉及通过活化的铝和水在氨（衍生物）存在下还原酮来制备胺。因为酮不与氨（衍生物）形成稳定的亚胺，所以不应该考虑这一点，而是使用相对温和的还原方法，因此酮可以转化成相应的胺。这是一个很好的方法，酮，甲胺和铝的使用量相当，甲基的收率是好的。每个人都知道用压力反应釜反应，提供3 atm氢气压

力应该不是大问题。通过苯基丙酮和甲胺的标准铝汞齐还原合成甲基苯丙胺，在3atm的氢气压力下这样做。在铝的水解过程中，原位生成所需的氢气是增加压力的必要条件。你只需要不断监测容器内氢气产生量及其压力。搅拌是必要的，但由于反应中使用了少量的铝，反应的时间可能很短。无论如何，这是实验的细节：苯基丙酮14部分，乙醚50部分，含20%甲胺乙醇15份，水5份，和2份活性铝3 atm磅的氢气压力下反应在一起。具体操作：向14g苯基丙酮溶解在50g乙醚中的溶液中加入15g 20％的甲胺醇溶液，

另外50g乙醚，5g水和2g活性铝。将混合物置于3atm的氢气压力下，当所有的铝都被消耗时，反应就完成了。通过过滤除去氢氧化铝，滤液用盐酸萃取。通过用碱性溶液中和，得到粗碱的14g，蒸馏得到纯的甲基苯丙胺。 方法2：盐酸甲胺氨化： 操作步骤：在1000ml宽口锥形烧瓶中，将19克切成3×3cm的铝箔在500ml氯化汞在700ml温水中的溶液中合并，直到溶液变灰，并以稳定的速率从铝表面。将水倾倒，用 2×500ml冷水洗涤铝汞齐。向铝汞齐中加入溶于30ml热水中的29.5g

苯基丙酮还原烷基化综述及文献

还原烷基化: 还原烷基化（醇胺化）与还原胺化有关。在还原胺化过程中，羰基化合物和氨形成一级胺；在还原烷基化过程中，一级或二级胺和羰基化合物的混合物分别形成二级或三级胺。以苯基-2-丙酮和甲胺为原料，采用还原烷基化法生产甲基苯丙胺。伯胺的烷基化过程与还原胺化过程相同——通过加成产物或通过亚胺（也称为席夫碱）水解。 1：催化加氢还原烷基化: 与还原胺化反应一样，还原烷基化反应依赖于羰基功能的反应性。胺的碱度也是一个因素。更碱性的胺通常优先与羰基功能反应（在没有空间位阻等因素的情况下）。因此，酮（如苯基-2-丙酮）将优先与更碱性的一级胺（如甲胺）反应，而不是较低碱性的二级胺反应产物（甲基苯丙胺也在空间上受阻）。铂氧化物或5%铂碳可能是这些反应的催化剂。在一些还原反应中，无论是碳上使用5%钯还是碳上使用铂，在吸收时间上似乎没有什么差别，但甲胺与苯基-2-丙酮利用钯的烷基化反应效果不佳（见下文）。有报道称，在还原烷基化之前应先还原铂氧化物。其他报告指出，无论是立即使用催化剂还是预还原催化剂，在许多可比反应中似乎没有任何差别。 当在碳或氧化铝上使用5%铑时，反应时间比铂或钯催化的烷基化反应长, 在弱酸存在下进行反应可以缩短反应时间。铑通常比其他催化剂效率低，但在含氯化合物存在下的烷基化反应中有价值，因为它通常不会导致脱氯。铑也可用于在酸性条件下溴存在下的烷基化反应。尽管一些报道了在低压下Raney镍存在下烷基化的良好结果，但在低

压下烷基化通常需要大量的催化剂。然而，雷尼镍在高温高压下通常是有效的。通过使用一种等量的醋酸来中和氮基对催化剂的影响，可以促进与Raney镍的低压还原烷基化（但是，请注意，碱性Raney镍催化剂通常比中性催化剂更为活跃）。雷尼镍的有效性也可能取决于其时间和活性。 （1）低压下氧化铂还原甲胺与1-苯基-2-丙酮的烷基化反应： 苯基-2-丙酮，68.5克（0.5摩尔）在150毫升乙醇中与51.8克（0.5摩尔）60%甲胺溶液反应，并在300 ATM压力下加140克铂氧化物加氢。存在一个12小时的滞后期，在此期间几乎没有或根本没有氢的吸收（催化剂的预还原没有改变滞后期）。此后，吸收通常在24小时内完成。在去除催化剂、浓缩滤液和洗涤液后，获得了外消旋N-甲基苯异丙胺（甲基苯丙胺）的高产率（90%或更高产率）。 （2）甲胺与1-苯基-2-丙酮经Raney镍高压还原烷基化反应： 用31.1 g（1.0摩尔）甲胺溶液在200 ml甲醇中处理134.2 g（1.0摩尔）苯基-2-丙酮。加入300g Raney镍合金后，在摇动或搅拌高压釜中在150C和1000atm下进行氢化。停止吸氢后，释放压力，过滤掉催化剂，蒸馏掉溶剂。残渣用10%盐酸酸化成刚果红（即pH6；pH3.0刚果红为蓝紫色，pH5.0刚果红），用乙醚萃取非碱性杂质。抛弃了醚提取物，并用有效的冷却，水溶液用10%氢氧化钠溶液制成碱，并用乙醚反复萃取。提取物用氢氧化钾干燥。溶剂蒸发后，通过20cm 的Vigreux柱蒸馏产物，获得80%的DL-1-苯基-2-甲基氨基丙烷收率，10mm汞柱。沸点193摄氏度。甲基苯丙胺最好以盐酸的形式储存。

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5 3）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

芳胺化反应-经典化学合成反应标准操作

经典化学合成反应标准操作 芳胺化反应 目录 一．前言 (1) 二．影响Buchwald 反应的因素及Buchwald 反应的应用 (2) 2.1 卤素对反应的影响............................................................................................................ 2.2 取代基团电子性对反应的影响....................................................................................... 2.3 配体对反应的影响............................................................................................................ 2.4 胺与苯基三氟甲磺酸酯的反应（Triflate） ................................................................. 2.5 对伯胺及仲胺的选择性.................................................................................................... 2.6 对手性的影响 .................................................................................................................... 2.7 与吡咯及吲哚的反应........................................................................................................ 2.8 关环反应............................................................................................................................. 2.9 卤代苯转化为苯胺反应.................................................................................................... 三．反应操作示例.............................................................................................. 3.1 典型操作一 ........................................................................................................................ 3.2 典型操作二 ........................................................................................................................ 四、参考文献 .....................................................................................................

氨基化指的是氨与有机化合物发生复分解而生成伯胺的反

第十章氨基化 10.1概述 氨基化指的是氨与有机化合物发生复分解而生成伯胺的反应，它包括氨解和胺化，氨解反应的通式可简单表示如下: R－Y+NH3一R－NH2+HY 式中R可以是脂基或芳基，Y可以是羟基、卤基、磺基或硝基等。 胺化是指氨与双键加成生成胺的反应则只能叫胺化。广义上，氨基化还包括所生成的伯胺进一步反应生成仲胺和叔胺的反应。 脂肪族伯胺的制备主要采用氨解和胺化法。其中最重要的是醇羟基的氨解，其次是羰基化合物的胺化氢化法，有时也用到脂链上的卤基氨解法。另外，脂胺也可以用脂羧酰胺或脂腈的加氢法来制备。 芳伯胺的制备主要采用硝化-还原法。但是，如果用硝化.还原法不能将氨基引入到芳环上的指定位置或收率很低时，则需要采用芳环上取代基的氨解法。其中最重要的是卤基的氨解，其次是酚羟基的氨解，有时也用到磺基～或硝基的氨解。 氨基化剂所用的反应剂主要是液氨和氨水。有时也用到气态氨或含氨基的化合物，例如尿素、碳酸氢胺和羟胺等。气态氨只用于气.固相接触催化氨基化。含氨基的化合物只用于个别氨基化反应。下面介绍液氨和氨水的物理性质和使用情况。 ①液氨液氨主要用于需要避免水解副反应的氨基化过程。用液氨进行氨基化的缺点是：操作压力高，过量的液氨较难再以液态氨的形式回收。 ②氨水对于液相氨基化过程，氨水是最广泛使用的氨基化剂。它的优点是操作方面，过量的氨可用水吸收，回收的氨水可循环使用，适用面广。另外，氨水还能溶解芳磺酸盐以及氯蒽醌氨解时所用的催化剂(铜盐或亚铜盐)和还原抑制剂(氯酸钠、间硝基苯磺酸钠)。氨水的缺点是对某些芳香族被氨解物溶解度小，水的存在特别是升高温度时会引起水解副反应。因此，生产上往往采用较浓的氨水作氨解剂，并适当降低反应温度。 用氨水进行的氨基化过程，应该解释为是由NH3引起的，因为水是很弱的“酸”，它和N地的氢键缔合作用不很稳定。 由于OH-的存在，在某些氨解反应中会同时发生水解副反应。 10.2卤素的氨解 10.2.1芳环上卤基的氨解 10.2.1.1反应历程 卤基氨解属于亲核取代反应。当芳环上没有强吸电基(例如硝基、磺基或氰基)时，卤

还原胺化反应综述

Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride.Studies on Direct and Indirect Reductive Amination Procedures1 Ahmed F.Abdel-Magid,*Kenneth G.Carson,Bruce D.Harris,Cynthia A.Maryanoff,and Rekha D.Shah The R.W.Johnson Pharmaceutical Research Institute,Department of Chemical Development, Spring House,Pennsylvania19477 Received January8,1996X Sodium 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. Introduction The 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 pH X 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,https://www.docsj.com/doc/a713665678.html,.React.1948,4,174and references therein.It was also proposed in hydride methods,see(b) Schellenberg,https://www.docsj.com/doc/a713665678.html,.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,https://www.docsj.com/doc/a713665678.html,.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 https://www.docsj.com/doc/a713665678.html,.Chem.1996,61,3849-3862 S0022-3263(96)00057-6CCC:$12.00?1996American Chemical Society

(完整word版)苯基丙酮还原胺化产物的酒石酸拆分研究

一：还原胺化反应的定义： 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。将羰基跟胺反应生成亚胺（席夫碱），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。还原胺化反应结束，后处理后我们得到的是外消体DL型甲基苯丙胺。而还原胺化得到的DL型甲基苯丙胺药效则要差很多，药效的差异是因为一个叫做“手性”的化学现象，而与纯度无关。正如人的左右手是各自的镜像一样，虽然外形一样，但其实是相反的，两种有机化合物也能以相互的镜像形式存在。由于甲基苯丙胺有一个手性中心，它有两种不同的称为“对映异构体”的镜像形式，也就是D型与L型，其中D型与L型各占一半。（按取代基的先后顺序来分是R型和S型，按与平面偏振光的作用来分是D型和L型， L是左旋，用-标识，D为右旋，用+标识，一般使用D型作为拆分剂）。因为平面的苯基丙酮—亚甲胺没有手性，因而氢加成在平面亚胺键两侧发生的几率是相同的。对映异构体一般有

着完全不同的生物效应，虽然它们看上去是一样的，在分子含量、结构以及外观上并没有区别，可以说完全一样，只是在紫外线的照射下，反射回来的光偏向不一样，往左偏的是“L型甲基苯丙胺”，往右偏的是“D型甲基苯丙胺”。但它们的作用形式并不总是一样的，主要在药效上不同。其中D 型甲基苯丙胺有典型的兴奋作用，而L型甲基苯丙胺的兴奋作用很弱，D型甲基苯丙胺对人体大脑中枢神经的兴奋作用是L型甲基苯丙胺的20倍。而甲基苯丙胺的对映异构体之间相互转化不是很容易，因为它手性中心上没有酸性氢。二：酒石酸的性质与用途介绍： 中文名:酒石酸 外文名:tartaric acid 分子质量:150.09 CAS号:87-69-4，526-83-0 简称:TA 状态:单斜晶体（无水） 英文别名：2,3-Dihydroxybutanedioic acid 熔点：171-174 密度：1.7598（20） 折光率：1.4955 溶解度：溶于水、丙酮、乙醇

氨解反应

氨解反应 氨解反应是指含各种不同官能团的有机化合物在胺化剂的作用下生成胺类化合物的过程。氨解反应包括卤素的氨解、羰基化合物的氨解、羟基化合物的氨解、磺基及硝基的氨解和直接氨解。 1定义 氨解反应是指含各种不同官能团的有机化合物在胺化剂的作用下生成胺类化合物的过程。可氨解的基团：－X，―OH，―SO3H，―CO―，Ar―H。 胺化剂：液氨、氨水、尿素、铵盐(NH3的来源)及有机胺。 合成胺类化合物的方法：反应类型，还原、氨解，水解，加成和重排。芳胺的两大制法，硝基还原(经济、方便)和芳环卤素氨解。 包括：卤素的氨解、羟基化合物的氨解、羰基化合物的氨解、磺基及硝基的氨解和直接氨解。2卤素的氨解 7.2.1 反应理论根据反应物的活泼性的差异，可分为非催化氨解和催化氨解 (1) 非催化氨解：对于活泼的卤素衍生物，如芳环上含有硝基的卤素衍生物，用氨水处理时，就可以使卤素被氨基置换。虽然不含磺基的芳香化合物在氨水中很难溶解，但大多数反应仍能在水相中进行，因为随着温和氨浓度的提高，氯化物在氨水中的溶解度会增大。ClNO2+NH3NH3ClNOO慢快-ClNH3NO2NH2NO2-H 反应历程 X +ArNH2NH2ArX NO2NO2NHAr 反应属于SN2历程，双分子亲核取代反应，首先是带有未共用电子对的氨分子向芳环与氯相连的碳原子发生亲核进攻，得到带有极性的中间加成物，此加成物迅速转化为铵盐，并恢复环的芳香性，最后脱掉质子，得到产物。第一步氨基衍生物的生成是决速步骤。 +HXNO2 动力学方程式：dc/dt = k c’ 式中c’为二硝基氯苯的浓度，当NH3大大过量时，为假一级反应。 反应历程的证明：通过一系列具有不同离去基团的卤素衍生物与同一亲核试剂反应反应的速度相比，如2，4－二硝基卤代苯和哌啶反应：XO2NNO2+NHNHO2NNO2X 当X为F、Cl、Br、I时，反应相对速率为：3300，4.3，4.3，1.0。证明C－X键的断裂对反应速率没有影响，否则C－X键的断裂为决速步骤，C－I的键最弱，反应速率为VRI>VBr>VRCl>VF。脂肪族取代属于这种情况。 (2) 催化氨解：对于活性较差的卤化物，如氯苯、1－氯萘－4－磺酸等，在没有铜催化剂存在时，在235℃，加压下与氨不会发生反应，但在铜催化剂存在时，200℃，便反应生成相应的芳胺。 主反应： A rC 副反应： ArClCu(NH3)2+ArOH+Cu(NH3)2++Cl-+OH- ArClCu(NH3)2+ArNHAr+Cu(NH3)2++HCl+ArNH2 研究发现：反应速度与铜催化剂及芳香氯化物的浓度成正比，与氨水的浓度无关。铜氨离子与芳香氯化物形成正离子络合物是反应速度的控制阶段。正离子络合物很快与氨、氢氧根离子或芳胺反应，分别得到主产物芳胺、副常委酚和二芳胺。主、副产物之比决定于氨，氢氧离子和芳胺的比例，氨浓度增加，可以减少酚和二芳胺的生成。 (3) 用氨基碱氨解：反应历程：当卤苯用KNH2在液氨中进行氨解反应时，是消除－加成反