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/cf3968388.html,.React.1948,4,174and references therein.It was also proposed in hydride methods,see(b) Schellenberg,https://www.docsj.com/doc/cf3968388.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/cf3968388.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/cf3968388.html,.Chem.1996,61,3849-3862

S0022-3263(96)00057-6CCC:$12.00?1996American Chemical Society

3-4it reduces aldehydes and ketones effectively,but this reduction becomes very slow at higher pH values.11At pH6-8,the more basic imines are protonated preferen-tially and reduced faster than aldehydes or ketones.10 This selectivity allows for a convenient direct reductive amination procedure.The literature is replete with publications that document the use of sodium cyanoboro-hydride in reductive amination reactions.12Limitations are that the reaction may require up to a fivefold excess of the amine,10is usually slow and sluggish with aromatic ketones10and with weakly basic amines,13and may result in the contamination of the product with cyanide.14The reagent is highly toxic15and produces toxic byproducts such as HCN and NaCN upon workup.

Other reported reductive amination reagents include borane-pyridine,13a Ti(OiPr)4/NaBH3CN,13b borohydride exchange resin,16a Zn/AcOH,16b NaBH4/Mg(ClO4)2,16c and Zn(BH4)2/ZnCl2.16d In addition,there are some reports of electrochemical reductive amination reactions.17

In our work on hydride-induced reductive aminations of aldehydes and ketones,we sought an alternative to the toxic sodium cyanoborohydride to eliminate the risk of residual cyanide in the product and in the workup waste stream,particularly for large scale reactions.Af-ter surveying many of the commercially available hy-dride reagents,we selected sodium triacetoxyborohydride [NaBH(OAc)3].18This borohydride reagent is mild and exhibits remarkable selectivity as a reducing agent.It reduces aldehydes selectively over ketones,18except for -hydroxy ketones which can be reduced selectively to give1,3-trans diols.19The steric and the electron-withdrawing effects of the three acetoxy groups stabilize the boron-hydrogen bond and are responsible for its mild reducing properties.20Our selection was also based on the results of reductive alkylation of amines using sodium borohydride in neat liquid carboxylic acids reported earlier by Gribble et al.21

In this paper we report the results of our comprehen-sive investigation of the scope and limitations of sodium triacetoxyborohydride in a procedure for direct reductive amination of aldehydes and ketones with a variety of aliphatic and aromatic amines.This report also includes an alternative stepwise route for the reductive amination of aldehydes with primary amines which involves the preformation of imines and their subsequent reduction with NaBH4in one-pot reactions.

Results and Discussions

The direct reductive amination reactions were carried out in1,2-dichloroethane(DCE),tetrahydrofuran(THF), or acetonitrile.The standard reaction conditions are as follows:a mixture of the carbonyl compound and the amine(0-5%molar excess)in the desired solvent is stirred with1.3-1.6equiv of sodium triacetoxyborohy-dride under a nitrogen atmosphere at room temperature. In some reactions,acetic acid(1-2mol equiv)is added to the mixture.The progress of the reaction is followed by GC and GC/MS analysis.The results from various reductive amination reactions of ketones and aldehydes are listed in Tables1and2,respectively.Solvents such as water or methanol are not recommended.Reactions in methanol resulted in a fast reduction of the carbonyl compound,and the reagent decomposed in water. (a)Reductive Amination of Ketones.The results in Table1show that the reductive amination of a wide variety of cyclic and acyclic ketones with primary and

(10)Borch,R.F.;Bernstein,M.D.;Durst,H.D.J.Am.Chem.Soc. 1971,93,2897.

(11)Borch,R.F.,Durst,H.D.J.Am.Chem.Soc.1969,91,3996.

(12)(a)Hutchins,R.O.;Natale,https://www.docsj.com/doc/cf3968388.html,.Prep.Proced.Int.1979, 11(5),201.(b)Lane,C.F.Synthesis1975,135.

(13)Occasional use of weakly basic or nonbasic amines was reported, see for example:(a)Pelter,A.,Rosser,R.M.,Mills,S.J.Chem.Soc., Perkin Trans.11984,717.(b)Mattson,R.J.,Pham,K.M.;Leuck,D. J.;Cowen,https://www.docsj.com/doc/cf3968388.html,.Chem.1990,55,2552.(c)Borch,R.F.;Hassid, https://www.docsj.com/doc/cf3968388.html,.Chem.1972,37,1673.(d)Marchini,P.;Liso,G.;Reho,A.; Liberatore,F.;Moracci,https://www.docsj.com/doc/cf3968388.html,.Chem.1975,40,3453.

(14)(a)The product from large scale reduction of the imine(i)with sodium cyanoborohydride was contaminated with cyanide.(b)A similar result was reported recently:Moormann,https://www.docsj.com/doc/cf3968388.html,mun.1993, 23,789.

(15)For information on the safety data and health hazards associ-ated with sodium cyanoborohydride see:The Sigma-Aldrich Library of Chemical Safety Data,1st ed.;Lenga,R.E.,Ed.,Sigma-Aldrich Corp.:Milwaukee,1985,p1609.

(16)(a)Yoon,N.M.;Kim,E.G.;Son,H.S.;Choi,https://www.docsj.com/doc/cf3968388.html,mun. 1993,23,1595.(b)Micovic,I.V.;Ivanovic,M.D.;Piatak,D.M.;Bojic, V.Dj.Synthesis1991,1043.(c)Brussee,J.;van Benthem,R.A.T.M.; Kruse,C.G.;van der Gen,A.Tetrahedron:Asymmetry1990,1,163.

(d)Bhattacharyya,S.;Chatterjee,A.;Duttachowdhhury,S.K.J.Chem. Soc.,Perkin Trans.11994,1.

(17)(a)Pienemann,T.;Schafer,H.-J.Synthesis1987,1005.(b) Smirnov,Yu.D.;Tomilov,https://www.docsj.com/doc/cf3968388.html,.Chem.U.S.S.R.1992,28(1), 42.(c)Smirnov,Yu.D.;Pavlichenko,V.F.;Tomilov,https://www.docsj.com/doc/cf3968388.html,.Chem. U.S.S.R.1992,28(3),374.

(18)(a)Gribble,G.W.;Ferguson, D. C.J.Chem.Soc.,Chem.

Commun.1975,535.(b)Nutaitis,C.F.;Gribble,G.W.Tetrahedron

Lett.1983,24,4287.(c)Gribble,G.W.In Encyclopedia of Reagents

for Organic Synthesis;Paquette,L.A.,Ed.,John Wiley and Sons:New

York,1995;Vol.7,p4649.

(19)See for example:(a)Saksena,A.K.;Mangiaracina,P.Tetra-

hedron Lett.1983,24,273.(b)Evans, D. A.;Chapman,K.T.

Tetrahedron Lett.1986,27,5939.(c)Evans,D.A.,Chapman,K.T.;

Carreira,E.M.J.Am.Chem.Soc.1988,110,3560.

(20)Gribble,G.W.;Nutaitis,https://www.docsj.com/doc/cf3968388.html,.Prep.Proced.Int.1985,17,

317.

(21)Earlier work by Gribble et al.demonstrated the potential of

triacyloxyborohydrides generated from NaBH4in neat liquid carboxylic acids in reductive alkylation of amines:(a)Gribble,G.W.;Lord,P.

D.;Skotnicki,J.;Dietz,S.

E.;Eaton,J.T.;Johnson,J.L.J.Am.Chem.

Soc.1974,96,7812.(b)Gribble,G.W.;Jasinski,J.M.;Pellicone,J.

T.;Panetta,J.A.Synthesis1978,766.

Scheme1

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secondary amines was successful under the standard conditions and gave the desired products in good to excellent yields.The scope of the reaction includes different alicyclic ketones,from cyclobutanone to cy-clododecanone(Table1:entries1-23),bicyclic ketones such as norcamphor and tropinone(Table1:entries24-30),saturated acyclic ketones(Table1:entries31-39), and keto esters(Table1:entries47-49).Nearly all primary and nonhindered secondary amines were used successfully in these reactions.For the same ketone,the rate of the reaction was dependent on the steric and electronic factors associated with the amines.In general, primary aliphatic amines reacted faster than primary aromatic and secondary aliphatic amines(Table1:en-tries10vs11;14and15vs16and17;24vs26and27). Cyclic secondary amines such as morpholine reacted faster than acyclic secondary amines such as diethyl-amine(Table1:entry33vs36)while the sterically hindered diisopropylamine did not react even after days (Table1:entry45).In some slow reactions(e.g.,Table 1:entries11,27,32,34,and36),small amounts of side products were formed(1-5%by GC area%analysis) from N-ethylation and N-acetylation of the starting amines.22These impurities were easily removed in the workup or during the recrystallization of the salts. The reaction conditions are very mild and can tolerate the presence of acid sensitive functional groups such as acetals and ketals.For example,the reductive amination of cyclohexanedione monoethylene ketal with primary and secondary amines afforded good to excellent isolated yields of the corresponding amines(Table1:entries14-18).Another example is the reductive alkylation of aminoacetaldehyde diethyl acetal with cyclododecanone (Table1:entry9).A particularly useful example is the reaction involving cyclohexanedione monoethylene ketal and aminoacetaldehyde diethyl acetal(Table1:entry18) which provides a secondary amine product containing protected aldehyde and ketone functionalities in a nearly quantitative yield.

Of all the ketones used in this study,small aliphatic cyclic ketones,ranging from cyclobutanone to cyclohex-anone,were most https://www.docsj.com/doc/cf3968388.html,rger cyclic ketones such as cyclooctanone and cyclododecanone and acyclic ketones such as2-heptanone reacted somewhat slower.Reactiv-ity of cyclobutanone was so high that its reaction with benzylamine gave a mixture of mono-and dicyclobutyl-benzylamines even with the use of excess amine(Table 1:entry2).Clean formation of N,N-dicyclobutylbenzyl-amine resulted with the use of a1:2molar ratio of amine to ketone(Table1:entry1).The reactions with second-ary amines were very effective since there was no dialkylation product(Table1:entry3).

The least reactive ketones were aromatic,R, -unsatur-ated,and sterically hindered ketones.Aromatic and R, -unsaturated ketones reacted very slowly(Table1:entries 40,41,and43).Experimentally,a saturated aliphatic ketone was reductively aminated,selectively,and quan-titatively in the presence of an aromatic or R, -unsatur-ated ketone(Table1:entries42and44).The unreacted ketones were recovered unchanged except for the forma-tion of trace amounts of their imines(as determined by GC/MS analysis of the reaction mixture).Sterically hindered ketones were even less reactive than aromatic and R, -unsaturated ketones,e.g.,camphor showed no reaction with benzylamine after four days(Table1:entry 46).The steric factors associated with both ketones and amines seem to be very important in determining the outcome of the reaction.

In reactions where the formation of diastereomers was possible,we observed varying degrees of selectivity. Reductive amination of4-tert-butylcyclohexanone with pyrrolidine and cyclohexylamine occurred with a moder-ate diastereoselectivity to give the thermodynamically less favored cis products.This results from equatorial attack by the hydride reagent on the intermediate imine, to form the axial amine(Table1:entries19and20).23 The reductive amination of androstanolone with isopro-pylamine gave a mixture of3R-and3 -(isopropylamino)-androstan-17 -ol in about25:75ratio(Table1:entry21). The reactions involving bicyclic ketones showed higher degrees of diastereoselectivity.For example,the reduc-tive aminations of norcamphor led to the exclusive formation of the endo products,from exo attack by the hydride reagent.The reductive amination of norcamphor with benzylamine(Table1:entry24)produced a single product.This product was identical to that obtained from the reductive amination of benzaldehyde with endo-2-aminonorbornane(Table2:entry13),thus confirming the endo stereochemistry of the product.

Reductive amination of tropinone with primary amines such as benzylamine and aniline(Table1:entries28and 29)was accomplished in good yield and high diastereo-selectivity giving the endo isomer as the major product (determined by1H NMR).24The reaction with benzyl-amine gave the endo and exo products in approximately 20:1ratio while the reaction with aniline showed no detectable exo product.The reaction of tropinone with piperidine was extremely sluggish giving low conversion to about a1:1mixture of the exo-and endo-products after four days of reaction(Table1:entry30).

The poor solubility of ammonium acetate in DCE,THF, or CH3CN limits its use in the reductive amination of ketones to prepare primary amines.The initial primary amine product is much more soluble than ammonium acetate and reacts faster with the ketone to generate dialkylamines,so this reaction can be used for the preparation of symmetrical dialkylamines.The amina-tion reaction is relatively slow and some ketone reduction may occur if AcOH is added.Even the use of a large excess(10equiv)of ammonium acetate in THF,DCE,or CH3CN,in the presence of Et3N,did not favor the formation of the monoalkylamine,the only product formed was dicycloheptylamine(Table1:entries22 and23).

N-Substituted R-amino esters were prepared by the reductive amination of R-keto esters with primary and

(22)The N-ethylation of amines is a major process in reaction of amines with sodium borohydride in neat acetic acid and is believed to proceed through an acetaldehyde formation.21a

(23)This result is consistent with literature reports on the reduction of4-substituted cyclohexanone imines or iminium salts which con-cluded that bulky hydride reagents such as L-Selectride attack preferentially from the less hindered equatorial side to give the cis-products,while less bulky hydride reagents such as NaBH4and NaBH3-CN slightly favor the axial approach,see:(a)Wrobel,J.E.;Ganem, B.Tetrahedron Lett.1981,22,3447.(b)Hutchins,R.O.;Markowitz, https://www.docsj.com/doc/cf3968388.html,.Chem.1981,46,3571.(c)Hutchins,R.O.;Su,W.-Y.; Sivakumar,R.;Cistone,F.;Stercho,https://www.docsj.com/doc/cf3968388.html,.Chem.1983,48,3412.

(d)Hutchins,R.O.;Adams,J.;Rutledge,https://www.docsj.com/doc/cf3968388.html,.Chem.1995, 60,7396.

(24)Chemical shift assignments of individual protons were arrived at by COSY,HETCOR,and Inverse HMBC NMR experiments.The stereochemistry of N-phenyl-3-aminotropane and N-benzyl-3-aminotro-pane was assigned based on1D NOE and coupling experiments.The assignments were in line with other literature reports;cf.Bagley,J. R.;Riley,T.N.J.Hetrocycl.Chem.1977,14,599and references therein.

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Table 1.Reductive Amination of

Ketones

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Abdel-Magid et al.

secondary amines.The reductive amination of methyl pyruvate with benzylamine was a fast and efficient reaction under the standard conditions that gave N -benzylalanine methyl ester in an excellent yield (Table 1:entry 47).The reaction was slower with hindered keto esters such as methyl 3-methyl-2-oxobutanoate (Table 1:entry 48),and the competing ketone reduction was a major reaction.The aromatic keto ester,methyl benzoyl formate reacted even slower with benzylamine and was also accompanied by considerable ketone reduction (Table 1:entry 49).Reactions involving other less reactive amines such as aniline or morpholine were much slower

Table 1.

(Continued)

Reductive Amination of Aldehydes and Ketones

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and gave increasing amounts of ketone reductions. Whenever ketone reduction was a problem,the conditions were modified to use the amines as limiting reagents. The excess ketones were completely reduced to the corresponding alcohols which required the occasional addition of excess reducing agent.N-Substituted R-ami-no esters were also prepared by the reductive amination of R-amino esters with ketones,e.g.,N-(2-butyl)glycine ethyl ester was prepared in very good yield from ethyl glycinate and2-butanone(Table1:entry50).

The reductive amination of cyclohexanedione mono-ethylene ketal with phenylhydrazine gave cleanly the N-substituted phenylhydrazine(Table1:entry51)in nearly quantitative yield.Other ketones such as cyclo-hexanone and2-heptanone reacted to give similar prod-ucts(Table1:entries52and53);however,there were some competing side reactions.The crude products showed the formation of byproducts,about15%with cyclohexanone and31%with2-heptanone.Attempted reductive amination of cyclooctanone with hydroxylamine was not successful and resulted in the oxime formation (Table1:entry54).

Reductive aminations in which diamines containing both primary and secondary amino groups were studied and in general,primary amines reacted faster.In the case where the primary amino group was aliphatic and the secondary group was aromatic,e.g.,N-phenylethyl-enediamine,there was a clear difference in reactivity between the two amines.The reaction with4-heptanone gave a quantitative yield of the product resulting from exclusive reaction with the primary amine(Table1: entry55).In the case where both amino groups were aliphatic,such as1-(2-aminoethyl)piperazine,there was a high selectivity(94:6)for the primary group in reaction with acetylcyclohexane(Table1:entry56).

(b)Reductive Amination of Aldehydes.Unlike ketones,aldehydes can be reduced with sodium triac-etoxyborohydride.18Thus,the possibility exists that the reduction of the aldehyde would compete with the reduc-tive amination process under the standard conditions. However,these conditions were so selective that the reductive aminations with aldehydes occurred very ef-fectively and resulted in fast reactions with no aldehyde reductions in most cases studied(Table2).One case in which aldehyde reduction was detected involved a reac-tion with the very sterically hindered diisopropylamine (Table2:entry6).All other examples in Table2resulted in fast and efficient reductive aminations with a variety of aliphatic primary and secondary amines as well as aniline with no detectable aldehyde reductions.Both aliphatic and aromatic aldehydes were very reactive and gave reductive amination products with a broad variety of primary and secondary amines.The reaction times ranged from20min to24h.The mildness of the reac-tion conditions is well illustrated in the reductive ami-nation of1,1′,2-tris-nor-squalene aldehyde with dieth-ylamine and diisopropylamine(Table2:entries19and 20).The aldehyde was cleanly converted to the corre-sponding amines in high yields with no detectable side reactions.

In the reductive amination of aldehydes with primary amines,formation of dialkylated amines is a common side reaction.5This side reaction was rarely a problem in most reactions reported in Table2.In the few cases when it was detected,it was suppressed by the addition of up to5%molar excess of the primary amine.However, the dialkylation of amines remained a problem with certain substrates.25An alternative stepwise procedure for such systems is discussed later in this paper. Some aldehydes,such as formaldehyde and glutaral-dehyde are only available commercially as aqueous solutions which may restrict their use under the above reaction conditions because of the decomposition of the hydride reagent with water.However,the reaction may be carried out in DCE with excess hydride reagent,e.g., the reductive amination of either aqueous glutaraldehyde or formaldehyde with1-phenylpiperazine and about4 hydride equivalents was carried out on10mmol scale (Table2:entries21and22)and gave nearly quantitative yields of the corresponding amines.This,however,may not be suitable for large scale reactions.

The use of phenylhydrazine in reductive amination of benzaldehyde was not successful,resulting only in hy-drazone formation.

Generally,with either ketones or aldehydes,reactions in DCE were noticeably faster than those carried out in THF(e.g.,Table1:entries6vs7;25vs26and Table2: entries3vs4;9vs10).Also,in the same solvent, reactions were consistently faster in the presence of1 (or more)mol equiv of acetic acid.For most ketones, reactions were improved in the presence of acetic acid. However,the addition of acetic acid is not always advantageous to the reaction.Most reactions with al-dehydes are fast and do not require addition of AcOH. Addition of AcOH to a slow reaction,e.g.,cyclohexan-ecarboxaldehyde with diisopropylamine,resulted in a fast reaction accompanied with about25%aldehyde reduc-tion,and the yield of the isolated desired product was only41%.When the reaction was carried out in the absence of AcOH,the reaction was slower;however,the aldehyde reduction was only about5%,and the isolated yield of the purified reductive amination product in-creased to75%(Table2:entries6and7).Direct com-parisons were made between reactions in DCE and THF and with or without added acetic acid in representative reactions.The rate of product formation was determined quantitatively26in each case.The results of these com-parisons were in agreement with the above observations.

(c)Reductive Amination with Weakly Basic and Nonbasic Amines.Few literature references have dealt with aromatic amines containing electron withdrawing substituents in reductive amination reactions.13,21a Cata-lytic hydrogenation conditions do not allow the presence of many of the easily reduced electron-withdrawing substituents such as cyano and nitro groups,since these substituents are often reduced under catalytic hydroge-nation conditions.6,7On the other hand,we and others13a,b have found the most used hydride reagent,sodium cyanoborohydride[NaBH3CN],to be sluggish and inef-ficient when used with these weak bases in reductive amination reactions.

As a consequence of substitution by electron-withdraw-ing substituents,these amines are both poor nucleophiles and weak bases(e.g.,p K a3.98for4-chloroaniline,1.02 for4-nitroaniline,-0.29for2-nitroaniline,-4.26for2,4-dinitroaniline).27This slows the initial nucleophilic at-

(25)For a discussion of the dialkylation side reactions involvingγ-andδ-amino esters with aldehydes and a mechanistic explanation, see:Abdel-Magid,A.F.;Harris,B.D.;Maryanoff,C.A.Synlett1994, 81.

(26)The progress of these reactions was followed by GC.Linear standard curves of the response factors by GC areas of starting materials and expected products were determined to allow the quantitative measurements of their concentrations in the reaction mixtures.

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tack on the carbonyl carbon and leads to slower overall reaction rates (Scheme 2).In addition,the carbonyl group now competes effectively with the less basic intermediate imine for protonation and subsequently for the hydride in the reduction step.2b This may lead to a significant carbonyl reduction,consumption of both the carbonyl compound and the reducing agent and low yields of the reductive amination products.The reducing agent and reaction conditions should be chosen carefully to minimize such side reactions.

Table 2.Reductive Amination of

Aldehydes

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Sodium triacetoxyborohydride is very efficient in re-ductive amination reactions with such unreactive amines. The results from several reactions are listed in Table3. In several cases such as monosubstituted anilines(e.g., p-nitro-p-carbethoxy-,and p-cyanoanilines),the standard reaction conditions described previously(about1:1ratio of carbonyl compound to amine,1.4equiv of NaBH(OAc)3 with1equiv of acetic acid)were adequate.However, with less basic amines such as o-nitroaniline,2,4-dichlo-roaniline,or2-aminothiazole,the reaction conditions were modified to compensate for the aforementioned effects and to maximize the yields of the reductive amination products.The optimum conditions included the use of the amine as the limiting reagent with1.5-2 mol equiv of the carbonyl compound,2-3equiv of NaBH-(OAc)3,and2-5equiv of AcOH in1,2-dichloroethane. Under these conditions,a variety of weakly basic amines were successfully employed in the reductive aminations of ketones and aldehydes in isolated yields ranging from 60%to96%.The reaction is convenient and the condi-tions are mild and show a high degree of tolerance for a variety of functional groups including nitro,cyano,halo, carboxy,and carbethoxy groups.

Ketones reacted effectively with p-monosubstituted anilines to give good yields of the reductive amination products(Table3:entries1-8).The reaction was slightly slower with2,4-dichloroaniline and gave a high yield of the desired reductive amination product in addition to some ketone reduction and the formation of about3%of N-ethyl-2,4-dichloroaniline(Table3:entry 9).The reaction became very slow with o-nitroaniline which progressed only to about30%conversion to the reductive amination product and17%of N-ethyl-2-nitroaniline after6days(Table3:entry10).The reaction stopped completely when both ortho positions were substituted as in2,6-dibromo-and2,4,6-trichloro-anilines(Table3:entries11and12).

The reactions with aldehydes were faster than those with ketones and gave higher yields from similar reac-tions.Aldehyde reductions occurred only with the least reactive amines.In the reductive amination of aldehydes with p-carboxyaniline and p-nitroaniline(Table3:en-tries13,14,and18),no competing aldehyde reduction was observed.In these cases,the standard conditions were used.With weaker amines such as2,4-dichloro-aniline and o-nitroaniline(Table3:entries15and16), the conditions were modified to use the amine as a limiting reagent since aldehyde reduction occurred to the extent of10-30%.This procedure was applied to other weakly basic primary amines such as2-aminothia-zole(Table3:entries22and23)and secondary amines such as iminostilbene(Table3:entry24).While imi-nostilbene reacted with hexanal to give a high yield of the N-hexyl product,the dihydro analogue iminodiben-zyl gave no reaction under the same conditions(Table3: entry25).

One of the most unique reactions,however,was the reductive alkylation of p-toluenesulfonamide with ben-zaldehyde to give the N-benzyl derivative(Table3:entry 26).The reaction is carried out initially under the standard conditions in the presence of Et3N(2equiv). The aldehyde is usually consumed in about24h to give a mixture of N-benzyl p-toluenesulfonamide and N-benzal p-toluenesulfonamide.The reaction mixture is then treated with AcOH(2.5equiv)and additional NaBH(OAc)3(1equiv)to finish the reduction.The reaction,however,was not successful with ketones or carboxamides.

The least reactive amines,2,4-dinitroaniline and2,4,6-trichloroaniline failed to undergo reductive amination with benzaldehyde(Table3:entries20and21).Cyclo-hexanecarboxaldehyde,on the other hand,reacted slowly with these two amines to give the corresponding reduc-tive amination products.In these two reactions,the aldehyde reduction became a major reaction process.To assure the presence of enough aldehyde to react with the amine,the reaction required occasional additions of aldehyde and reducing agent,up to5equiv each and over a two to four day period(Scheme3).The reactions progressed to reach90-92%conversion(as determined by GC)and gave61%and58%isolated yields,respec-tively,after chromatography.It is possible that these reactions proceed via initial formation of intermediate enamines rather than imines which may explain the lack of reactivity of aromatic aldehydes which cannot form enamines.

(d)Comparison with Other Reducing Agents.In general,the results of reductive amination employing sodium triacetoxyborohydride were as good as or better than most comparable reported results whether done using hydrogenation or hydride reagents.However,in many cases,our results were far superior to others.For example,we compared the reductive amination of cyclo-hexanone with morpholine using NaBH3CN vs NaBH-(OAc)3.The reaction with NaBH3CN(6hydride equiv) in methanol and in the absence of AcOH was only34% complete after23h with the formation of about10%of the corresponding enamine.The conversion improved to 50%in23h with AcOH(1equiv)with no enamine formation.The reaction using the standard NaBH(OAc)3 conditions was99.8%complete in3h without a trace of enamine formation(Table1:entry5).In another comparison,the reductive amination of1-carbethoxy-4-piperidinone with p-chloroaniline was only45%complete with NaBH3CN after22h but was>96%with NaBH-(OAc)3in2.5h(Table3:entry4).

An impressive result was obtained in the reductive amination of1,1′,2-tris-nor-squalene aldehyde with di-ethylamine and isopropylamine.These reactions were reported to give about5%yield under regular Borch conditions.28The yields were improved to46and42%, respectively,when the reactions were carried out with NaBH3CN in anhydrous THF in the presence of HCl(pH 3).29Under our standard conditions,these reactions gave

(27)(a)Albert,A.;Serjeant,E.P.In The Determination of Ionization Constants;Chapman and Hall:London,1971;p91.(b)Yates,K;Wai, H.J.Am.Chem.Soc.1964,86,5408.

(28)Duriatti,A.;Bouvier-Nave,P.;Benveniste,P.;Schuber,F.; Delprino,L.;Balliano,G.;Cattel,L.Biochem.Pharmacol.1985,34, 2765.

(29)Ceruti,M.;Balliano,G.;Viola,F.;Cattel;L.;Gerst,N.;Schuber,

F.Eur.J.Med.Chem.1987,22,199.

Scheme2

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98and 90%yield of products in high purity without chromatography (Table 2:entries 19and 20).

The reductive amination of either 2-indanone, -te-tralone,or phenylacetone with aniline was reported to work when aniline was used as solvent under catalytic hydrogenation conditions and gave 72%,54%,and 21%yield of products,respectively.30We obtained 85%,87%,and 80%yield of these products using stoichiometric

amounts of reagents under the standard conditions (Table 1:entries 12,13,and 38).

Borane -pyridine is another reducing agent used for reductive amination reactions.13a Its use in the reductive amination of either pyridine-4-carboxaldehyde or m -nitrobenzaldehyde with ethyl piperidine-2-carboxylate

(30)Campbell,J.B.;Lavagnino,E.P.In Catalysis in Organic Syntheses ;Jones,W.H.,Ed.;Academic Press:New York,1980;p 43.

Table 3.Reductive Amination with Weakly Basic

Amines

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gave12%and13%yield of isolated reductive amination products,respectively,and considerable aldehyde reduction.14b Under our standard conditions,we did not observe any aldehyde reduction,and the isolated yields were nearly quantitative(Table2:entries17and18).

(e)Stepwise(Indirect)Reductive Amination of Aldehydes.Occasionally,some reactions of aldehydes and primary amines gave considerable amounts of di-alkylation or other side products.As we mentioned previously,the addition of a slight excess of the primary amine may suppress this side reaction.However,the dialkylation of certain primary amines such asγ-or δ-amino esters and cyclobutylamine,remained a problem. This also occurred when certain aldehydes were used, such as cinnamaldehyde,hydrocinnamaldehyde,and some straight chain aldehydes.Those particular cases gave mixtures of monoalkylated and dialkylated amines in ratios ranging from5:1and up to1:1under the standard reaction conditions.Surprisingly,in some reactions,the dialkylation side reaction happened even when excess amine was used or when the reaction was carried out with a“preformed imine”and no excess aldehyde present.A discussion and a possible explana-tion of some of these results in case ofγ-andδ-amino esters was reported.25We developed an alternative procedure for such reactions which involves the fast reduction of preformed imines.Imine formation,how-ever,is a reversible reaction and requires long reaction times and the use of a dehydrating agent such as molecular sieves or azeotropic removal of water to drive the reaction to completion.We studied the relative rates of imine formation from aldehydes and primary amines in different solvents,namely THF,DCE,and methanol without added catalysts or dehydrating agents.A com-parison of the relative rates of imine formation in the three solvents is listed in Table4.The relative ratio of product imine to reactant aldehyde was determined by GC analysis of the reaction mixture and confirmed in some cases by1H NMR in CD3OD,THF-d8,or CDCl3.In all the cases listed in Table4,reactions in methanol were consistently faster and gave nearly quantitative conver-sions relative to those carried out in THF or DCE.The imine formation was slower for ketones in all three solvents;however,the reaction was still faster in metha-nol(Table4:entry7).

The reduction of the aldimines was carried out directly in methanol with sodium borohydride to give the corre-sponding secondary amines in very high yields and very short reaction times.Thus,this stepwise(or indirect) one-pot procedure involving imine formation in methanol followed by in situ reduction with sodium borohydride is a very convenient and efficient alternative for carrying out reductive aminations on substrates which tend to give significant amounts of dialkylated products using the direct procedure.

A similar transformation along the lines of prior formation of the imine is prior formation and then reduction of the enamine.We have found that sodium triacetoxyborohydride reduces enamines quickly and efficiently in DCE to give products in high yields(Table 5:entries6and7),making it a useful reagent for this stepwise procedure.

Another very efficient stepwise reductive amination procedure was developed by Mattson et al.13b In this procedure,the amine and the carbonyl compound are mixed in neat titanium(IV)isopropoxide and the result-ing intermediate is reduced with NaBH3CN in ethanol. The authors reported the formation of a carbinol amine intermediate(see Table5:entries8-10)rather than the usual iminium ion.The method is applicable to primary and secondary amines.We modified this procedure to reduce the intermediate with NaBH4in methanol(in-stead of NaBH3CN/ethanol).31This modified reduction is very fast and gives the desired amine in very good yield and high purity,e.g.,the reductive amination of the unsaturated ketone1-acetylcyclohexene with benzyl-lamine,which was very slow under our standard condi-tions,proceeded very fast under these modified conditions to give a quantitative yield of the reductive amination product(Table5:entry8).Of particular interest,the reductive amination of tropinone with benzylamine using this procedure which gave a near quantitative yield of a 3:2mixture of the endo-and exo products(Table5:entry 10).As reported earlier,this reaction gave approximately 20:1ratio of the endo and exo products using NaBH(OAc)3 (Table1:entry28).Attempts to achieve a reaction between tropinone and aniline using this modified system resulted in incomplete reactions.In regards to secondary amines,Mattson et al.13b reported a successful reductive amination of tropinone with piperidine in58%yield; however,the stereochemistry of the product was not disclosed.Our modified conditions gave the product in a90%crude yield as a mixture of the endo-and exo-products in about1:7ratio.The pure oxalate salt of the exo product was isolated in66%yield(Table5:entry9). The exo-stereoselectivity of this reaction is opposite to that obtained from the primary amines.We are examin-ing these systems to better understand their mechanistic pathway.

Summary and Conclusions

The results presented here indicate that sodium tri-acetoxyborohydride is a synthetically useful reagent for reductive aminations of aldehydes and ketones.It is a mild,commercially available reagent,and it is a reagent of choice for reductive amination of carbonyl compounds. The scope of the reaction covers all aldehydes and unhindered aliphatic ketones.Aliphatic ketones(and aldehydes)can be selectively reductively aminated in the

(31)(a)We reported the use of this modification of Mattson’s procedure(Ti(OiPr)4-NaBH4/MeOH,rt)at the198th ACS National Meeting,Miami Beach,FL,September1989;paper ORGN154and at The International Chemical Congress of Pacific Basin Societies, Honolulu,HI,December1989;paper ORGN409,Abdel-Magid,A.F.; Maryanoff,C.A.;Sorgi,K.L.;Carson,K.G.A similar modification [Ti(OiPr)4-NaBH4in diglyme at60°C or in ethanol at25°C)]was reported recently:(b)Bhattacharyya,S.Tetrahedron Lett.1994,35, 2401.(c)Bhattacharyya,S.Synlett1994,1029;(d)Bhattacharyya,S. https://www.docsj.com/doc/cf3968388.html,mun.1995,25,9.

Scheme3

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presence of aromatic and R , -unsaturated ketones.Ali-phatic and aromatic primary and sterically unhindered secondary amines can be used in these reactions.The procedure was superior with weakly basic and nonbasic amines.In representative comparisons with other com-monly used reducing reductive amination reagents,sodium triacetoxyborohydride reacted consistently faster,gave better yields,and produced fewer side products.Methanol allows a rapid formation of imines from alde-hydes and primary amines.Aldimines formed in metha-

nol were efficiently reduced to their corresponding amines using NaBH 4.

Experimental Section

Melting points are uncorrected.1H NMR and 13C NMR spectra were recorded at 400MHz.The chemical shifts are expressed as δunits with Me 4Si as the internal standard.IR spectra were recorded on an FT-IR spectrometer and absorp-tions are reported in wave numbers (cm -1).GC-MS (EI)were recorded on a GC/MSD instrument using a cross linked methyl

Table 4.Imine Formation from Aldehydes and Primary Amines

Yield (%)

Entry Aldehyde Amine

Time (h)by GC (solvent)by 1H NMR (solvent)

1benzaldehyde tert -BuNH 22284(DCE)80(CDCl 3)2295(THF)98(THF-d 8)497(MeOH)97(CD 3OD)2benzaldehyde aniline 4.281(DCE)90(CDCl 3)4.374(THF)75(THF-d 8)1.599(MeOH)97(CD 3OD)

3m -anisaldehyde aniline

2492(DCE)2684(THF)2.499(MeOH)4m -anisaldehyde 2-(3,4-dimethoxyphenyl)ethylamine 297(DCE)100(CDCl 3)0.2495(THF)100(THF-d 8)0.2598(MeOH)100(CD 3OD)

5c-C 6H 11CHO aniline 5.489(DCE)5.390(THF)2.796(MeOH)6c-C 6H 11CHO tert -BuNH 2 4.689(DCE)5.390(THF)2.794(MeOH)7

cycloheptanone

benzylamine

2353(DCE)2375(THF)23

85(MeOH)

Table 5.Stepwise Reductive Amination

Reactions

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silicone12m×0.2mm×0.33mm capillary column.Mass spectra were recorded as CI or FAB.Accurate mass measure-ments were carried out using a double-focusing instrument of EB configuration(where E is an electric sector and B is a magnet).The reported accurate mass(mass-to-charge ratio) measurement values(mean(3σ)are for the[MH]+ions of the analytes of interest and are the average of nine individual determinations.The deviation of the experimental determina-tions from the theoretical values are expressed in parts-per-million(ppm).GC analyses were carried out on a cross linked methyl silicone12m×0.2mm×0.33μm capillary column or DB-17;15m×0.2mm×0.25μm.Sodium triacetoxyboro-hydride was purchased from Aldrich Chemical Company,Inc. Most reagents were commercially available reagent grade chemicals and used without further purification.

Procedures. 1.Direct Reductive Amination Methods. General Notes.(a)The amine and the carbonyl compound are mixed in1,2-dichloroethane and treated with NaBH(OAc)3. THF,CH2Cl2,or CH3CN may also be used as solvents.

(b)Acetic acid(1-2mol equiv)may be used in reactions of ketones but is not necessary with most aldehydes.

(c)Reactions are normally carried out using the free amines; however,the amine salt may be used.In this case,1-2equiv of Et3N is added to the reaction mixture.The Et3N must be removed from basified product prior to salt formation.

(d)The progress of the reaction is followed by GC analysis in most cases.A small aliquot is withdrawn from the reaction mixture,quenched with aqueous NaOH or aqueous NaHCO3 and extracted with ether or any other suitable solvent and injected into the GC.In case of high MW or heat-sensitive compounds HPLC or TLC could be used.

(e)The reactions are usually quenched with aqueous1N NaOH.In the presence of esters,or other alkali hydroxide sensitive functional groups,aqueous NaHCO3is used for quench.Reactive amines such as benzylamine may dissolve in aqueous NaHCO3and that may give a false indication of their consumption.

(f)Most amines form HCl salts cleanly in ether with ethereal HCl,and most of these salts are recrystallized from EtOAc/ MeOH.Some aromatic HCl salts may turn dark and a few aliphatic amine salts may be difficult to crystallize or may be hygroscopic;in these cases the oxalate salts are prepared, usually in MeOH.Picrate salts are prepared in ethanol.

Method I.This procedure is used for most ketone reactions.

A representative example is the reductive amination of cyclo-pentanone with hexamethyleneimine(Table1:entry4): Hexamethyleneimine(1.0g,10mmol)and cyclopentanone (0.84g,10mmol)were mixed in1,2-dichloroethane(35mL) and then treated with sodium triacetoxyborohydride(3.0g, 14mmol)and AcOH(0.6g,10mmol).The mixture was stirred at rt under a N2atmosphere for24h until the reactants were consumed as determined by GC analysis.The reaction mixture was quenched by adding1N NaOH,and the product was extracted with ether.The ether extract was washed with brine and dried(MgSO4).The solvent was evaporated to give the crude free base(1.60g,96%).The oxalate salt was prepared in EtOAc/MeOH as shiny white crystals(2.2g, 85.5%):mp171-172°C;FT-IR(KBr)3435(w),2934(s),2872 (m),2683(m),2648(m),2585(m),2524(m),1720(m),1623 (m),1455(m),1404(m),1204(m),1116(m),717(m),499(m), 466(m)cm-1;1H NMR(free base,CDCl3)δ2.94-2.83(m,1H), 2.68-2.65(m,4H),1.87-1.25(m,16H);13C NMR(free base, CDCl3)δ65.9(CH),53.6(CH2),30.2(CH2),27.9(CH2),26.9 (CH2),24.1(CH2);EI MS m/z(relative intensity)167(M+,15), 138(100),124(17),110(24),96(9),82(7),55(16).Anal.Calcd for C13H23NO4:C,60.68;H,9.01;N,5.44.Found:C,60.69; H,9.03;N,5.44.

Method II.The above procedure is followed without the addition of glacial acetic acid.The reaction mixture remains cloudy throughout the reaction.This procedure is more appropriate with most aldehydes and unhindered aliphatic ketones.A representative example is the reductive amination of4-pyridinecarboxaldehyde with ethyl2-piperidinecarboxylate (Table2:entry17):Ethyl-2-piperidinecarboxylate(1.57g,10 mmol)and4-pyridinecarboxaldehyde(1.07g,10mmol)were mixed in1,2-dichloroethane(35mL)and then treated with sodium triacetoxyborohydride(3.0g,14mmol).The mixture was stirred at rt under a N2atmosphere for1.5h.The GC analysis showed>90%conversion in30min,but the remain-der of the time was needed for the complete conversion.The reaction mixture was quenched by adding aqueous saturated NaHCO3,and the product was extracted with EtOAc.The EtOAc extract was dried(MgSO4),and the solvent was evaporated to give the crude free base(2.40g,96.7%),>98% pure by area%GC analysis.A small portion was converted to the dioxalate salt:an off-white solid,mp109-111°C (EtOAc/MeOH);FT-IR(KBr)3076(w),2968(w),2870(w),2521 (m),1738(s),1603(s),1504(m),1460(w),1372(w),1204(s), 999(w),714(m)cm-1;1H NMR(free base,CDCl3)δ8.52(d,J )5.2Hz,2H),7.29(d,J)5.2Hz,2H),4.19(q,J)7.1Hz, 2H),3.80(d,J)14.4Hz,1H),3.43(d,J)14.4Hz,1H),3.20 (m,1H),2.90(m,1H),2.20(m,1H),1.85(m,2H),1.55(m, 3H),1.45(m,1H),1.28(t,J)7.1Hz,3H);13C NMR(free base, CDCl3)δ174.1(C),153.3(C),149.7(CH),125.8(CH),64.8 (CH),61.8(CH2),59.9(CH2),51.0(CH2),30.5(CH2),26.4(CH2), 23.1(CH2),15.8(CH3);EI MS m/z(relative intensity)175(M+ -CO2Et,100),147(4),93(5),92(25),82(5),65(15).Anal. Calcd for C18H24N2O10:C,50.47;H,5.65;N,6.54.Found:C, 50.26;H,5.74;N,6.44.

Method III.Same as Method I except for using THF as a solvent.An example is the reductive amination of2-heptanone with morpholine(Table1:entry33):2-Heptanone(2.28g, 20mmol)and morpholine(1.92g,22mmol)were mixed in THF(80mL)at rt under N2.Sodium triacetoxyborohydride (6.36g,30mmol)and glacial AcOH(1.20g,20mmol)were added,and the mixture was stirred at rt for27h.The reaction mixture was quenched with aqueous saturated NaHCO3 solution,and the product was extracted with Et2O.The Et2O extract was dried(MgSO4)and cooled in an ice bath and then treated with ethereal HCl.The product precipitated as a white solid.The solid was collected by filtration and dried;yield: 3.24g,73%(>98%by GC area%analysis)mp150-151°C. The analytical sample was obtained as a white crystalline solid by recrystallization from EtOAc/MeOH:mp151-153°C;FT-IR(KBr)3410(m),2924(s),2863(s),2656(s),2604(s),2462 (m),1434(m),1266(m),1114(s),1073(m),928(m),881(m); 1H NMR(CDCl3)δ12.60(bs,1H),4.43(dt,J)12.8,2.1Hz, 2H),3.98(dd,J)12.8,3.0Hz,2H),3.30-3.16(m,3H),3.09-2.95(m,2H),2.15-2.06(m,1H),1.64-1.10(m,10H),1.44(d, J)6.7Hz,3H),0.90(t,J)6.5Hz,3H);13C NMR(CDCl3)δ63.43(CH2),63.37(CH2),62.5(CH),47.9(CH2),47.4(CH2), 31.2(CH2),30.0(CH2),25.8(CH2),22.2(CH2),13.7(CH3),13.4 (CH3);EI MS m/z(relative intensity)185(M+,5),170(28), 115(31),114(100),86(7),84(7),70(28).Anal.Calcd for C11H24ClNO:C,59.58;H,10.91;N,6.32;Cl,15.99.Found: C,59.66;H,11.00;N,6.42;Cl,16.09.

Method IV.Same as method II except for using THF as a solvent.An example is the reductive amination of -tetralone with cyclohexylamine(Table1:entry10):Cyclohexylamine (1.09g,11mmol)and -tetralone(1.46g,10mmol)were mixed in THF(50mL)at rt under N2.The mixture changed in about 1min from yellow to dark blue in color.Sodium triacetoxy-borohydride(3.18g,15mmol)was added and the mixture stirred at rt under a N2atmosphere for24h.The color of the reaction mixture became light pink at the end of the reaction time.The reaction mixture was quenched by adding aqueous 3N NaOH(the color changed to dark green),and the product was extracted with Et2O.The Et2O extract was dried(MgSO4) and cooled in an ice bath and then treated with ethereal HCl. The product precipitated as a white solid with a light pink shade.The solid was collected by filtration and dried;yield: 2.27g,85%(>98%by GC area%analysis).The analytical sample was obtained as a white solid by recrystallization from EtOAc/MeOH:mp230-233°C;FT-IR(KBr)3415(s),2941 (s),2819(s),2679(m),2506(w),2430(w),1452(m),742(m) cm-1;1H NMR(CDCl3)δ9.60(bs,2H),7.16-7.02(m,4H), 3.62-3.45(m,1H),3.43-3.12(m,3H),2.91-2.80(m,2H), 2.61-2.50(m,1H),2.40-2.17(m,3H),1.91-1.60(m,6H), 1.39-1.18(m,3H);13C NMR(CDCl3)δ134.6(C),132.4(C), 129.2(CH),128.6(CH),126.5(CH),126.1(CH),54.2(CH),51.0 (CH),32.3(CH2),29.5(CH2),28.9(CH2),27.9(CH2),26.0(CH2), 24.7(CH2);EI MS m/z(relative intensity)229(M+,46),187

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(13),186(85),158(12),132(11),131(77),130(100),129(34), 128(20),116(14),115(26),104(23),100(17),91(35),78(11), 77(12),56(28),55(31).Anal.Calcd for C16H24ClN:C,72.29; H,9.10;N,5.27;Cl,13.34.Found:C,72.41;H,9.27;N,5.17; Cl,13.53.

Method V.This method is similar to methods I and II except for the use of acetonitrile as a solvent.

Method VI.This method was used with those reactions involving hindered R-keto esters or weakly basic amines in which a competitive reduction of the carbonyl compounds occur.The amine is used as a limiting reagent.A representa-tive example of the R-keto esters is the reductive amination of methyl3-methyl-2-oxobutanoate with benzylamine(Table 1:entry48):methyl-3-methyl-2-oxobutanate(1.8g,12.48 mmol)and benzylamine(0.446g,4.16mmol)in DCE(14mL) was treated with sodium triacetoxyborohydride(1.76g,8.32 mmol)at0°C.After stirring21h,GC analysis showed total consumption of the benzylamine with the presence of the product amine and the intermediate imine in an8:1relative ratio.The reaction was then treated with additional sodium triacetoxyborohydride(0.88g,4.16mmol).After stirring an additional21h,GC analysis showed completion of the reaction. The reaction mixture was diluted with EtOAc(20mL)and quenched with distilled water(10mL).After further dilution with EtOAc(20mL),the pH of the water layer was adjusted to7with saturated aqueous NaHCO3.The EtOAc layer was separated and dried(MgSO4).The solvent was removed under reduced pressure to give the crude product(2.45g).The crude product was dissolved in ether and treated with ethereal HCl to give the HCl salt,0.92g,81%yield,as a white solid:mp 190-191°C;FT-IR(KBr)2966(m),2806(m),2696(m),1742 (s),1565(m),1469(m),1424(m),1249(s),1030(m),753(m), 704(m)cm-1;1H NMR(CDCl3)δ10.65(bs,1H),10.00(bs1H), 7.66-7.63(m,2H),7.41-7.38(m,3H),4.40(d,J)13.3Hz, 1H),4.25(d,J)13.3Hz,1H),4.20(q,J)7.1Hz,2H),3.45-3.35(m,1H),2.75-2.60(m,1H),1.30(t,J)7.1Hz,3H),1.15 (d,J)6.9Hz,3H),1.09(d,J)6.9Hz,3H);13C NMR(CDCl3)δ166.7(C),130.9(CH),129.5(CH),129.0(CH),63.1(CH), 62.2(CH2),50.3(CH2),29.4(CH),19.5(CH3),17.6(CH3),14.0 (CH3);CI MS m/z(rel intensity)236(MH+,100),162(38),91 (20).Anal.Calcd for C14H22ClNO2:C,61.87;H,8.16:N,5.15. Found:C,61.94;H,8.21:N,5.05.

An example of the use of weakly basic amines is the reductive amination of1-Carbethoxy-4-piperidone with p-nitroaniline(Table3:entry5):1-Carbethoxy-4-piperidone(3.2 g,19mmol),p-nitroaniline(1.4g,10mmol),and glacial AcOH (3.6g,60mmol)were mixed in1,2-dichloroethane(45mL). Sodium triacetoxyborohydride(6.0g,28mmol)was added to the above solution and the reaction mixture stirred at room temperature under N2for18h(GC analysis indicated a complete reaction in addition to ca20%ketone reduction).The reaction was quenched with saturated aqueous NaHCO3,and the product was extracted with EtOAc(3×75mL).The EtOAc extract was dried(MgSO4),and the solvent was evaporated to give a yellow semisolid(4.7g).The semisolid was triturated with ether/hexane(7:3)to disolve the excess piperidone and the piperidol byproduct.The yellow solid was collected by filtration and dried(1.75g,60%),>99%pure by GC area%analysis.The analytical sample was obtained by recrystallization from EtOAc/hexane:mp172-174°C;FT-IR (KBr)3327(s),3182(w),3097(w),2929(w),2870(m),2398 (m),1679(s),1600(s),1546(m),1460(s),1387(m),1296(s), 1234(m),1184(m),1144(m),1105(s),1033(m),937(m);1H NMR(CDCl3/d6-DMSO)δ8.03(d,J)9.0Hz,2H),6.59(d,J )9.0Hz,2H),6.14(d,J)7.5Hz,1H),4.16-4.10(m,4H), 3.58-3.50(m,1H),3.02(m,2H),2.04-2.00(m,2H),1.51-1.42(m,2H),1.27(t,J)7.0Hz,3H);13C NMR(CDCl3/d6-DMSO)δ154.9(C),152.5(C),136.4(C),125.9(CH),110.6 (CH),60.8(CH2),49.0(CH),41.9(CH2),31.0(CH2),14.2(CH3); MS(EI),293(95),277(15),276(76),264(9),248(12),220 (23),177(19),156(29),155(100),154(9),131(10),130(23), 129(16),128(13),127(37),126(41),117(14),100(21),96 (19),82(28),57(18),56(57).Anal.Calcd for C14H19N3O4:C, 57.33;H,6.53;N,14.33.Found:C,57.27;H,6.54;N,14.21.

2.Stepwise Procedures.Aldimine Formation/Reduc-tion in Methanol.An example is the preparation of N-cy-clobutyl-4-chlorobenzylamine(Table5:entry4):p-Chloroben-zaldehyde(1.40g,10mmol)and cyclobutylamine(0.75g,10.6 mmol)were mixed in MeOH(40mL)at rt under a N2 atmosphere.The mixture was stirred at rt for3h,until the aldimine formation was completed(determined by GC).The aldimine in MeOH was carefully treated with solid NaBH4(0.6 g,16mmol).The reaction mixture was stirred for10min and quenched with1M NaOH.The product was extracted with ether.The ether extract was washed with saturated aqueous NaCl and dried(MgSO4).The solvent was evaporated to give the crude product as a nearly colorless oil(1.92g,98%)which was>97%pure by area%GC analysis.The oil was dissolved in ether and treated with ethereal HCl to give the HCl salt which was recrystallized from EtOAc/MeOH as white crystals, 2.07g,89%,mp237-238°C;FT-IR(KBr)2917(s),2804(s), 2762(s),2435(m),1497(m),1432(m),1092(m),808(m),520 (m)cm-1;1H NMR(free base,CDCl3)δ7.25-7.22(m,4H),

3.64(s,2H),3.28-3.21(m,1H),2.23-2.16(m,2H),1.71-1.63 (m,4H),1.38(bs,1H);1H NMR(HCl salt,CDCl3+CD3OD)δ9.70(bs,1H),7.50(d,J)8.4Hz,2H),7.37(d,J)8.4Hz, 2H),3.94(s,2H),3.52(q,J)8.15Hz,1H),2.95(bs,2H),2.41-2.35(m,2H),2.22-2.13(m,2H),1.99-1.89(m,1H),1.83-

1.73(m,1H);13C NMR(free base,CDCl3)δ138.9(C),13

2.4

(C),130.1(CH),129.4(CH),50.2(CH),53.4(CH2),30.9(2CH2),

14.6(CH2);EI MS m/z(relative intensity)196(M+),167(48), 125(100),89(26),39,(18).Anal.Calcd for C11H15Cl2N:C, 56.91;H,6.51;N,6.03;Cl,30.54.Found:C,56.89;H,6.45; N,5.87;Cl,30.82.

Reduction of Enamines.An example is the reduction of 1-morpholino-1-cyclohexene(Table5,entry6and Table1, entry5):1-Morpholino-1-cyclohexene(1.67g,10mmol)in DCE(30mL)and AcOH(0.61g,10mmol)was treated with sodium triacetoxyborohydride(3.0g,14mmol)and stirred under argon.The GC analysis determined that the reduction was complete after10min.The reaction was quenched by adding1M NaOH,and the product was extracted with ether. The ether extract was dried(MgSO4),and the solvent was evaporated under reduced pressure to give the crude product as a colorless oil(1.70g).The oil was dissolved in ether(50 mL),cooled in an ice bath,and treated with ethereal HCl to give the HCl salt as a white solid.The solid was collected by filtration air-dried,and then recrystallized from EtOAc/MeOH to give the purified product(1.88g,91.4%):mp260-262°C. Picrate salt:a yellow solid,mp174-175°C(ethanol)(lit.11 176-177°C);FT-IR(HCl salt,KBr)3425(s),2937(s),2861 (m),2672(s),2606(s),2478(m),1448(m),1399(w),1267(w), 1110(s),1070(w),950(w)cm-1;1H NMR(free base,CDCl3)δ3.74(t,J)5.0Hz,4H),2.43(t,J)5.0Hz,4H),2.29(m,1H), 1.88(d,J)10.0Hz,4H),1.61(d,J)13.0Hz,1H),1.28(m, 5H);13CNMR(free base,CDCl3)δ66.9(CH2),63.4(CH),49.3 (CH2),28.4(CH2),25.9(CH2),25.4(CH2);EI MS m/z(relative intensity)169(M+,16),127(11),126(100),98(7),83(10),82 (12),68(10),56(19),55(36).Anal.Calcd for C10H20ClNO: C,58.38;H,9.80;N,6.81;Cl,17.23.Found:C,58.22;H,9.69; N,6.72;Cl,17.25.

The Use of Titanium(IV)Isopropoxide.An example is the synthesis of N-[1-(1-cyclohexenyl)ethyl]benzylamine(Table 5,entry8):1-Acetylcyclohexene(1.24g,10mmol)and benzylamine(1.2g,11.2mmol)were mixed in neat titanium-(IV)isopropoxide(4.78g,16.8mmol)and stirred under nitrogen for3h.Methanol(45mL)was added followed by careful addition of NaBH4(0.6g,16mmol).Analysis of the reaction mixture after5min by GC indicated a complete reduction to the amine.The reaction was quenched by adding 0.1N NaOH.The resulting mixture was filtered through Celite,and the residue was washed with ether(2×50mL) and with CH2Cl2(50mL).The organic layer was separated and dried(MgSO4).The solvent was removed under reduced pressure to give the crude product(2.2g).The crude product was dissolved in ether and treated with ethereal HCl to give the HCl salt as a white solid.The solid was purified by recrystallization from EtOAc/MeOH to give2.1g,83%,of white crystals:mp215-217°C;FT-IR(KBr)3417(m),2932(vs), 2835(m),2782(s),2732(s),2481(w),2422(w),1581(m),1454 (m),1381(w),748(m),680(m)cm-1;1H NMR(CDCl3)δ9.65 (bs,1H),7.61(d,J)7.4Hz,2H),7.35(t,J)7.4Hz,2H),

Reductive Amination of Aldehydes and Ketones https://www.docsj.com/doc/cf3968388.html,.Chem.,Vol.61,No.11,19963861

7.29(d,J)7.0Hz,1H),5.73(s,1H),3.95-3.92(m,1H),3.78-3.72(m,1H),3.44(bs,1H),2.25-2.21(m,1H),2.05-1.95(m, 3H),1.72-1.51(m,4H),1.52(d,J)6.8Hz,3H);13C NMR (CDCl3)δ132.6(C),130.6(CH),130.5(C),129.9(CH),128.9 (CH),128.7(CH),59.0(CH),48.3(CH2),25.1(CH2),23.8(CH2), 22.2(CH2),21.9(CH2),17.4(CH3);EI MS m/z(relative intensity)215(M+,4),201(16),200(83),134(17),109(4), 108(4),105(10),93(5),92(13),91(100),79(13),77(11).Anal. Calcd for C15H22ClN:C,71.55;H,8.81;N,5.56;Cl,14.08. Found:C,71.73;H,8.92;N,5.40;Cl,13.96. Acknowledgment.We are grateful to the PRI spectroscopy group for their help and assistance: D. Gauthier,G.Leo,and P.McDonnell for NMR spectra, J.Masucci and W.Jones for the FT-IR and mass spectra,and X.Xiang,D.Burinsky,and R.Dunphy for the high resolution mass spectra.We also thank Dr. Norman Santora,the chemical information specialist, for his valuable help with the library search.We thank professor Robert O.Hutchins(Drexel University)for helpful discussions and for supplying some authentic samples.

Supporting Information Available:Supporting data for nearly all products are available including mp,FT-IR,1H NMR,13C NMR,MS,and elemental analysis(39pages).This material is contained in libraries on microfiche,immediately follows this article in the microfilm version of the journal,and can be ordered from the ACS;see any current masthead page for ordering information.

JO960057X

https://www.docsj.com/doc/cf3968388.html,.Chem.,Vol.61,No.11,1996Abdel-Magid et al.

(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：

文献综述城市规划

文献综述城市规划 IMB standardization office【IMB 5AB- IMBK 08- IMB 2C】

浅谈城镇建设存在的问题与未来 姓名：李里 摘要：在阅读多篇文章以后，总结出中国目前新城镇建设存在的普遍问题，由于追求快速城镇化，造成城市建设与城市空间都存在问题，同时建设时并没有考虑保护环境这一方面。目前，生态城市成为最新的城市改造建设模式，取代了传统的城市建设模式。 关键词：城镇建设，生态城市，海绵城市，低碳城市 一、城镇建设存在的问题 目前，新城建设中突出的问题是：新城求洋求新，导致千城一面的城市，形象特色危机；大拆大建导致的生态环境破坏和历史文脉隔断；部分新城人气不足，活力缺少，建设成效与期望差距甚远；过于关注形象和规模，新城认为不足，配套缺失；不够重视经济测算，造成一定的财政负担，前期投入多，后期收效不大。 不少城市的领导为了追求任期业绩，既不尊重投入产出规律，也不考虑经济效果和创新，更不考虑资金的回收问题。对老城区部分青红皂白一律推到重建，这是一种最原始、最不科学、最粗野的城市更新方式，造成一些有保留价值的建筑、设施、古木、风貌等的破坏，是城市的有形和无形资产严重受损，甚至完全消失。城市文脉是一座城市在长期建设中形成的历史的、文化的、特有的、地域的、景观的氛围和环境，是一种历史和文化的积淀。目前，城市中普遍存在着低水平的、低层次的简单城市更新，不注重保护和延续城市的文脉，是城市的文脉收到认为的破坏和割裂。城市正在走向雷同，特有风貌消失。随着世界经济一体化进程的加快和信息、文化、科技各个领域交流的扩大，城市更新改造中大量地运用了新技术、新工艺、新材料、新的设计理念大大促进了城市更新的进程和步伐。但是由于各地“追风”现象十分严重，效仿和追大潮成为时尚，是城市更新中出现了雷同，城市正在被克隆，正在失去领域的、文化的、传统的、多样化的特色，建筑正在失去个性和灵魂。在城市更新改造中，将保护建筑视为获得眼前利益的捷径，千方百计的肆意

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。

城市化与经济增长关系研究的文献综述

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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/cf3968388.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)，

中国城市化发展战略研究

ＧＲＯＵＰＥＣＯＮＯＭＹ 集团经济研究２００６? ４下半月刊（总第１９６期）城市化是伴随着工业化的进程而向前推进的。我国１９４９年城市化水平只有１２％左右。新中国成立后城市化在曲折中发展，至１９７８年城市化水平不超过１７．９％。经过改革开放 ２０多年的发展，到２００３年城市化水 平达到４０．５％。由于经济过剩的压力和企业开工不足造成的下岗压力等原因，现在我们重新开始审视过去走过的城市化道路。与工业化程度相比较，我国的城市化已经滞后了，而且已经影响到了我国经济结构的进一步提升，阻碍了中国的现代化进程。所以，如何进一步推进城市化，是我国当前和今后一段时期内的重要经济任务。 一、 我国城市化进程的回顾我国的城市化经历了一个曲折的过程。新中国建国之初，毛泽东曾明确认识到需要通过工业化带动城市化。随着工业化的推进，从１９５２年至１９５７年，我国城市人口增加了 ３０００万。接着，因“大跃进”而引起的 经济衰退，使我们在１９６２－１９６５年间进行了经济调整，在减少工业项目，压缩基本建设规模的同时，减少城市人口，并提出提高建制镇的标准，减少市镇数量。此后，至８０年代初，我国的城市化进程缓慢，甚至出现了城市数量减少的“逆城市化”现象，大城市由１１５个减少为１０５个，小城镇由５４００个减少为２９００个。由于建国以后实行计划经济体制，企图把一切经济活动都纳入国家计划的范围，包括对于城市化问题上也是采取计划的方式。从５０年代以后，一系列的政策如：户籍管理制度、城市劳动用工、农村人口进入城市完全由国家计划，国家试图有计划地逐步推进城市化， 致使中国的城市化远远落后于中国的工业化进程。我国城市化没能顺利推进、城市化滞后于工业化，主要有两个原因：其一，从客观上看，我国推进的是以重工业体系为主的工业化，属资本密集型，虽然也能吸收劳动就业，但在这种模式下劳动所占的份额较少，存在着资本对劳动的替代问题。所以，当时虽然从表面上看是政府规定不允许农村人口进入城市寻找工作，但实际上是因为城市并没有创造出更多的就业岗位。如果城市里存在足够多的工作岗位，政府就会号召人们进入城市就业。其二，从主观上看，舆论过度渲染了发达国家城市化带来的问题和城市化完成以后出现的人口逆向流动的趋势，也过度渲染了一些发展中国家城市化中所出现的问题，因此想通过人口的有计划迁移来避免城市化，特别是大城市发展所带来的负面影响，如城市失业、贫困、犯罪问题和交通、污染等问题。 我国的城市化进程涉及到一个对城市化道路认识的方法论问题。社会经济的发展是一个自然历史过程，尽管政府的力量是极其强有力的，但它也不能任意取消或者改变这个自然的发展历程。 改革开放以后，由于家庭联产责任制的推广，农业生产中新的激励机制实施后生产率的提高，使农村中出现了更多的富余劳动力。本来，按照正常的经济发展规律，农村的推力和城市的拉力将会引起城市化速度的加快。但因我国改革具有渐进性的特点，改革初期城市中计划经济仍然占有绝对地位，所以，从农村中走出来的劳动力“离土不离乡”、“进厂不进城”，走了发展乡镇企业之路。 乡镇企业的发展，形成了中国特殊的城市化道路—— —城镇化。到目前为止我国已经形成了大约１９０００个建制镇。应当肯定，在城乡隔绝的社会结构体制下，在城市工业生产力水平较低的条件限制下，小城镇为依托的城市化发展战略对于促进社会经济发展特别是农村人口生活水平的提高有积极的意义。但是，小城镇城市化的起点太低，乡镇布局星罗棋布，比较分散，有的城镇只有三四千人，城镇人口数量不足使商业和服务业难以发展。城镇虽小，但医院、学校都要五脏俱全，基础设施和社会事业建设的投资效益低下，造成社会资源的极大浪费。而城镇规模小的另一个方面，是难于进行有效的基础建设和环境污染治理，公共物品难以积累，于是在不少地方，“村村象城镇，镇镇像农村”。各小镇都以劳动密集型产业为基础，地方保护主义造成生产要素在城镇之间的流动壁垒，使企业之间难于合并和资产重组，产业同构现象严重，相互之间恶性竞争，削弱了进一步发展的潜力。同时，小城镇缺乏现代大工业最基本的规模效益和最起码的交通、通讯、供电等社会生产条件，现代工业很难发展起来，也抑制了第三产业的发展。同时，我们在考察世界各国城市化道路时发现，城镇化仅仅是城市化的初始表现形态，而且，城市化在初始阶段与工业化相联系，当实现工业化以后，进一步的城市化又与产业结构的升级具有直接的关系。所以，我们现在在充分肯定城镇化的巨大历史和现实作用的同时，也明确我们应进入城市化的更高阶段。 二、当前阻碍进一步城市化的体制因素 中国城市化发展战略研究 文／卢旭东 战略研究 ４７

(完整word版)战斗应激反应

战斗应激反应 军事文献中用来描述士兵在战场上出现的心理、精神障碍的名词很多，例如：“炮弹休克”、“战争精神症”、“战斗衰竭”、“战斗应激”、“战斗应激反应”等。人们很早就注意到了士兵在战争中出现的心理、精神上的异常，有文字记载的第一例这类减员是战场癔症性失明，出现在公元前490年的马拉松战役中。希腊史学家Herodotus是这样描述的：雅典人Epizelus异常勇猛，但在马拉松混战之后却丧失了视觉。奇怪的是他的身上没有任何受到损伤或被击中的痕迹，而眼睛却什么也看不见了，且其整个后半生都是如此。Epizelus认为自己失明的原因是当时看到一个非常粗壮的男人就在面前。那是个胡子长得把整个盾牌都遮住丁的怪物，他猛冲过来一下子杀死了站在自己身边的一个人。一瞬间，Epizelus的整个世界一片漆黑。由于当时是冷兵器时代，主要减员原因是刀箭伤，战场情况对士兵的心理压力不大，故这类战场癔症性减员的数量很少，没有引起应有的重视。在美国内战、日俄战争，两次世界大战等战争中，精神性减员数量的增加使人们逐渐认识到了了解这种精神异常的重要性，并开始对士兵在战场上出现的影响战斗力的心理、精神异常表现的本质进行探索，其认识过程可以分为以下3个阶段： 一、将此类心理、精神异常视为“贪生怕死”的阶段 这个阶段虽然没有一个精确的开始时间，但是我们可以认为自从有了军队、军纪和战争，该阶段就开始了。这是在战场这个特殊的条件下形成的，尤其是战斗最激烈的时刻，完全有理由将士兵现精神心理障碍看成“贪生怕死”的表现，是一种违反战时纪律的行为，因而这时的士兵应该被送到战时的军事法庭，按照违反战时军纪处理。在各个国家的军队中都出现过这种情况，所以这种“违反军纪”是一种比较普遍的、自然的认识。通常对这类士兵的处罚比较严厉，如：将这些士兵关进监狱，强迫其加入“突击队”，甚至处决。美国南北战争期间，白人部队中有3％的士兵因患严重的“思乡症”而失去了战斗力，并被以“违反军纪”的罪名处决，但这种办法并未能降低“思乡症”的发病率。在现代战争中，“违法军纪”的观点仍被很多军事人员所坚持。究其原因，除了对这个问题的本质认识不清外，还有一个原因就是真正的违纪行为与心理应激性违纪行为之间的界限不易确定。 二、将此类心理、精神异常视为“精神病”的阶段 l8世纪，一些法国军医最早意识到这是一个重要的军事精神医学问题。他们了解到，部分受到军事法庭审判的士兵(其中包括一些违反纪律的士兵甚至逃兵)所受到的审判是不公正的。因为这些士兵存在着病态的心理障碍，故而不能理智地对待错误，或者不能控制自己的错误行为，所以是不应该受到审判的。于是在l759年，法军建立了一所医院，专门收治那些怀疑其违纪犯罪行为是一种精神疾病表现的士兵。此后，有心理障碍的士兵就不再因其违反了纪律而受到军法制裁了。由于战时出现的精神异常表现与日常人们见到的精神疾病表现十分相似，所以法国军医提出“精神疾病”本质论，得到了广泛的赞同。但是，以此理论为指导的军事精神病学保障工作却遇到了很多难。例如，在1905年的日俄战争中，俄军一方发生大量的精神病减员现象，俄军将领认为这是一个应该重视的重要军事医学问题，于是在哈尔滨设立了一所精神病中心医院。这里每天可以接收43～90名病员，但经过l5天的治疗，病员中只有极少数在短期内归队，在收容的275名军官中就有2l4名被后送，l072名士兵中有983名被后送。从日俄战争的例子中可以看出，将战时的精神性减员按平常的精神疾病性减员处理，虽然使士兵免遭军法制裁，但并没有真正解决问题，仍然流失了大量的有作战指挥技能的军事人才。 三、将战时心理、精神异常视为“应激”的阶段 第一次世界大战期间，美军的ThomasSalmon博士提出处理此类伤员“及时、就处理战时精神异常人员的三原则。这个里程碑标志着“精神疾病”的阶段发展到了高潮，也标志着应激阶段的开始。三原则提出以后，大量的战争心理医学保障的经验教训主要是对精神异常本质的探索。第二次世界大战及第四次中东战争中有很多事实表明：当战斗激烈到一定程度的时候，任何人都可能出现精神异常。通过对这类减员的观察研究，人们发现减员的主要原因是战场环境因素一应激源一造成士兵的心理生理适应障碍。战场的环境因素主要有战斗的激烈程度、指挥官的组织指挥能力、部队凝聚力的强弱等等。还有一个重要的战场环

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。

社交焦虑文献综述

四川师范大学 科学硕士（教育硕士）研究生专业课程学期考试专用封面 学期考试课程名称： 社会性发展专题研究 考试时间： 2011 年 月 日 任课教师打分： 任课教师签名： 年 月 日 ___ __教育科学学院___ __ 学院___ _1 0_ _级__ 发展与教育心理学_ _专业 姓名 刘会兰__ 学号_201 00 4040202005 …… … … … … … … … … … …（ 密 ） …… … … …… … … …… … … （ 封 ） … ……… … …… … … …… … （ 线） … … … … … … ………………

认知行为疗法对社交焦虑的干预研究文献综述 摘要：焦虑是一种普遍存在的人类体验，一定水平的焦虑对于个体保持正常的功能是必需的，但过分的焦虑将干扰个体的正常功能而成为病态的状况。社交焦虑是焦虑障碍中常见的一种损害社会功能的、影响相当数量人口的心理疾患，又称社交恐怖症或者社交焦虑障碍。本文主要从社交焦虑、认知行为疗法、社交焦虑的干预这几个方面进行文献综述。 关键词：社交焦虑，认知行为疗法，干预。 1 社交焦虑 1.1 社交焦虑的界定 社交焦虑的提出可以回溯1846年CasPer报道的赤面恐怖。1903年，法国精神病学家Janet第一个对社交焦虑进行描述，所用词为“社交恐怖”或“社会的恐怖症”，并将其归为神经衰弱一类。本世纪伊始，stocke:将其称之为“社会神经症”，并记载于病例中.最早提出“社交焦虑”一词的是英国精神病学家Markaeelder(1966年)，他根据发病年龄以及害怕的对象不同，从恐怖障碍中区分出一组称之为社交焦虑(Soca11Anxiety)的病人，他们的表现是害怕社交处境，如害怕在众人前脸红、说话、吃东西，害怕参加聚会等等。1970年，Mark:修改完善了他的理论，提出了社交恐怖症(Soeialphobia)的概念，以之代替了“社交焦虑”，并指出其基本特征是害怕自己在社交处境中被别人认为是可笑的。由于当时行为主义的兴盛，人们对于社交焦虑的研究兴趣随之不断地升温。行为主义治疗家们仍然以社交焦虑这一