Mannichreacion曼尼希反应PPT课件

Published:August 10,2011NOTE/jocOrganocatalytic Asymmetric Domino Aza-Michael ÀMannich Reaction:Synthesis of Tetrahydroimidazopyrimidine DerivativesHong Li,†Junling Zhao,*,†Lili Zeng,†and Wenhui Hu*,†,‡†Guangzhou Institute of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou Science Park,Guangdong 510530,People ’s Republic of China ‡State Key Laboratory of Respiratory Disease,Guangzhou,Guangdong 510120,People ’s Republic of ChinabSupporting Information The tetrahydroimidazopyrimidine ring system is found in many naturally occurring products that have attracted attention due to the broad scope of their biological activities.1,2Di fferent classes of tetrahydroimidazopyrimidine compounds have shown antidepressant 2a,b and antihypertonia 2c activities that have been put to pharmaceutical uses.However,syntheses of tetrahydroimidazopyrimidine derivatives are not very well documented in the literature.2b,3The traditional methods for their synthesis often require many synthetic manipulations and puri fications,which result in low overall yields.Thus the devel-opment of novel,concise methodologies that allow the rapid construction of these tetrahydroimidazopyrimidine skeletons,preferably in a single operation,is highly desired.Organocatalytic domino reactions 4À6allow the sequential formation of several new bonds and chiral centers in just one operation.They have been proven to be powerful tools for the e fficient and stereoselective synthesis of complex molecules 7that are di fficult to access by traditional methods.The aza-Michael addition 8participated domino reaction provides a simple and direct way for the synthesis of nitrogen-containing heterocycles.For example,the asymmetric syntheses of 1,2-dihydroquin-olines,9pyrrolidines,10tetrahydro-1,2-oxazines,11and iso-indolines 12have been realized.Herein,we report the first asymmetric synthesis of enantioenriched tetrahydroimidazopyr-imidine derivatives through an organocatalytic domino strategy using R ,β-unsaturated aldehydes and N -arylidene-1H -imidazol-2-amines as starting materials (Scheme 1).The reactions of 2-carbonyl-substituted indoles 13and pyrroles 14with enals have been realized for the syntheses of pyrrolidine-fused heterocycles.However,the asymmetric synth-esis of six-membered ring-fused heterocycles,such as biologically interesting tetrahydroimidazopyrimidines,through aza-Michael reaction of nitrogen heterocycles has not been reported.We would like to focus our research on this challenging task.Unlike tetrazole,triazole,and other nitrogen heterocycles,15the N ÀHgroup of imidazole is not acidic enough to participate in N-alkyaltion reactions.The introduction of electron-withdrawing groups,such as carbonyl or cyano,can reduce the p K a value of this N ÀH group,making it possible for N-alkylation reactions 13,14,15b to occur.The iminic group is a weak electron-withdrawing group and enables many further transformations.We envisaged that the N -arylidene-1H -imidazol-2-amines (1)and the R ,β-unsaturated aldehydes (2)might be suitable substrates for the domino aza-Michael ÀMannich reaction and that they would generate the highly substituted tetrahydroimidazopyrimidine derivatives (3).To test our hypothesis,the readily available L -proline-derived secondary amines (I ÀIV ),which are capable of both iminium 16and enamine 17catalysis,were explored as catalysts for this domino reaction.The reaction of N -benzylidene-1H -imidazol-2-amine (1a )and cinnamaldehyde (2a )was selected as a model reaction.We first studied catalysis of the domino reaction with diphenyl prolinol silyl ether (I )in dichloromethane.The reaction pro-ceeded with high stereoselectivity (97%ee,>20:1dr)but in low yield (30%,Table 1,entry 1).There was no signi ficant improve-ment in yield when using a variety of di fferent solvents,mostScheme 1.Domino Aza-Michael ÀMannich Reaction of r ,β-Unsaturated Aldehyde and N -Arylidene-1H -imidazol-2-amineReceived:June 22,2011ABSTRACT:Highly substituted tetrahydroimidazopyrimidine derivatives with three chiral centers have been synthesized for the first time using an organocatalytic asymmetric domino aza-Michael ÀMannich reaction of R ,β-unsaturated aldehydes and N -arylidene-1H -imidazol-2-amines.This e fficient approach fur-nishes the products in good yields (42À87%)with excellent stereoselectivities (>20:1dr,up to >99%ee).likely due to the poor solubility of 1a in these solvents.However,high stereoselectivities were retained (Table 1,entries 2À5).When methanol was used as solvent,the starting material 1a was completely consumed in just 6h to provide the product 3a in 55%yield and 96%ee (Table 1,entry 6).The arylaldehyde and 2-aminoimidazole derived from the decomposition of 1a also were detected.Those results suggested that 1a was more active in methanol and that the use of a mixture of dichloromethane and methanol might improve the e fficiency of the reaction.Experi-ments indicated that this was the case.After extensive screening,the best results in terms of yield (73%)and enantioselectivity (99%)were obtained using a 9:1ratio of dichloromethane and methanol (Table 1,entry 7).The yield was improved to 80%by the addition of benzoic acid while retaining high enantioselec-tivity (>99%ee,Table 1,entry 9).In contrast,the addition of sodium acetate had almost no in fluence on the reaction (Table 1,entry 11).Other secondary amine catalysts also were examined as catalysts:the reaction proceeded in 42%yield and 99%ee when catalyst II (Table 1,entry 12)was used,and there were no domino reaction product detected in 24h when catalysts III and IV were employed (Table 1,entries 13and 14).With the optimal reaction conditions in hand,the substrate scope of this domino aza-Michael ÀMannich reaction was ex-plored,and the results are summarized in Table 2.Various substituted aromatic enals were examined.Both electron-with-drawing and electron-donating groups on the aromatic ring weretolerated,yielding the expected products in moderate to high yields (54À80%)and excellent stereoselectivities (>97%ee,>20:1dr,Table 2,entries 1À12).The reaction of 2-furyl and 2-thiophene enal led to the formation of 3m and 3n in 49and 42%yields,respectively,both in 99%ee (Table 2,entries 13and 14).The electronic nature of the substituent on the aromatic ring of 1had little in fluence on the reaction.Extensions of this strategy to use the less reactive aliphatic enals were unsuccessful;no reaction occurred when crotonaldehyde was used.The absolute con figuration of the three new chiral centers of 3n was assigned as 5S ,6S ,and 7R by X-ray crystallographic analysis of 4n (the alcohol corresponding to 3n ,Figure 1).On the basis of this observation,a plausible catalytic cycle for the reaction is proposed in Scheme 2.The reaction starts with the iminium activation of 2by I ,followed by aza-Michael addition of 1to the iminium ion to give intermediate A .The enamine of A undergoes an intramolecular Mannich reaction to give B .The catalyst is regenerated for the next catalytic cycle through hydrolysis of B :B then hydrolyzes to give tetrahydroimidazo-pyrimidine 3.In summary,we have developed a novel organocatalytic domino aza-Michael ÀMannich reaction of N -arylidene-1H -imi-dazol-2-amines and R ,β-unsaturated aldehydes for use in the synthesis of highly substituted tetrahydroimidazopyrimidineTable 2.Substrate Scopeof the Domino Aza-Michael ÀMannich Reaction aentry R 1R 2yield b (%)dr c ee d (%)1Ph (1a )Ph (2a )803a >20:1>992Ph (1a )3-MeC 6H 4(2b )713b >20:1993Ph (1a )3-OMeC 6H 4(2c )503c >20:1>994Ph (1a )3-ClC 6H 4(2d )603d >20:1995Ph (1a )3-BrC 6H 4(2e )683e >20:1>996Ph (1a )3-NO 2C 6H 4(2f )703f >20:1997ePh (1a )4-MeC 6H 4(2g )583g >20:1998Ph (1a )4-MeOC 6H 4(2h )543h >20:1>999ePh (1a )4-ClC 6H 4(2i )763i >20:19810e Ph (1a )4-BrC 6H 4(2j )723j >20:19811ePh (1a )4-NO 2C 6H 4(2k )763k >20:1>9912Ph (1a )piperonyl (2l )663l >20:19913Ph (1a )2-furyl (2m )493m >20:19914Ph (1a )2-thiophene (2n )423n >20:199154-OMeC 6H 4(1b )4-ClC 6H 4(2i )603o >20:198164-OMeC 6H 4(1b )4-NO 2C 6H 4(2k )623p >20:19717e 4-CF 3C 6H 4(1c )Ph (2a )853q >20:199184-CF 3C 6H 4(1c )4-ClC 6H 4(2i )873r >20:19919e4-CF 3C 6H 4(1c )4-NO 2C 6H 4(2k )753s>20:199aReactions was performed with N -arylidene-1H -imidazol-2-amine (0.13mmol),R ,β-unsaturated aldehyde (0.1mmol),I (0.02mmol),and PhCOOH (20mol %)in DCM/MeOH (9:1,0.3mL)at room temperature.b Isolated yield.c Determined by 1H NMR of the products.dDetermined by HPLC analysis with the corresponding alcohol.eDCM/MeOH (1:1)as solvent.Table 1.Optimizing of the Reaction Conditions aentry catalyst solvent time (h)yield b (%)dr c ee d (%)1I DCM 2430>20:1972I THF 2430>20:1953I toluene 24trace ND ND 4I ether 24trace ND ND 5I CHCl 32420>20:1986I MeOH655>20:1967I DCM/MeOH (9:1)1673>20:1998I DCM/MeOH (1:1)1277>20:1989e I DCM/MeOH (9:1)1680>20:1>9910f I DCM/MeOH (9:1)1273>20:19811e II DCM/MeOH (9:1)2442>20:19912e III DCM/MeOH (9:1)24NR 13eIVDCM/MeOH (9:1)24traceNDNDaReactions was performed with N -benzylidene-1H -imidazol-2-amine (0.13mmol),cinnamaldehyde (0.1mmol),and secondary amine (0.02mmol)in solvent (0.5mL)at room temperature.b Isolated yield.cDetermined by 1H NMR of the products.d Determined by HPLC analysis with the corresponding alcohol.e With 20%PhCOOH as additive.f With 20%NaOAc as additive.derivatives bearing three chiral centers.The reaction is catalyzed e fficiently by readily available diphenylprolinol silyl ethers with moderate to good yield (42À87%)and high stereoselectivities (>97%ee,>20:1dr).This strategy described could be extended to the asymmetric synthesis of biologically important tetrahy-dropyrazolopyrimidine derivatives 18and other tetrahydropyri-midine-fused heterocycles.’EXPERIMENTAL SECTIONGeneral Procedure for the Preparation of 1a À1c.To asolution of benzaldehyde (1.92mL,18.8mmol)in dichloromethane (15mL)were added sequentially 2-aminoimidazole sulfate (3.7g,14.3mmol),tetraisopropyl orthotitanate (6.83mL,23.3mmol),and triethylamine (3.9mL,28.1mmol).The reaction mixture was stirred at room temperature for 24h and then concentrated in vacuo.The residue was taken up in ethyl acetate and water and filtered.The filtrate was separated,and the organic phase was dried over anhydrous sodium sulfate and concentrated.The crude product was recrystallized from ethyl acetate/hexane to afford 1a 19in 60%yield:1H NMR (400MHz,DMSO-d 6,ppm)δ12.23(s,1H),9.15(s,1H),7.95(m,2H),7.58À7.50(m,3H),7.15(br s,1H),6.93(br s,1H).N -(4-Methoxybenzylidene)-1H -imidazol-2-amine (1b).The title compound was obtained according to general procedure described above in 50%yield:1H NMR (400MHz,DMSO-d 6,ppm)δ12.17(s,1H),9.08(s,1H),7.89(d,J =8.8Hz,2H),7.07(d,J =8.8Hz,2H),7.0(br s,2H),3.83(s,3H);13C NMR (125MHz,DMSO-d 6,ppm)δ162.6,159.2,151.4,130.9,128.9,114.9,55.9;HR-MS (ESI)m /z 202.0979[M +H]+,calcd for C 11H 12N 3O,202.0980.N -(4-(Trifluoromethyl)benzylidene)-1H -imidazol-2-amine (1c).The title compound was obtained according to general proceduredescribed above in 70%yield:1H NMR (400MHz,DMSO-d 6,ppm)δ12.49(s,1H),9.24(s,1H),8.14(d,J =8.0Hz,2H),7.85(d,J =8.0Hz,2H),7.19(br s,1H),6.99(br s,1H);13C NMR (125MHz,DMSO-d 6,ppm)δ157.9,150.5,139.7,131.4(q,J C ÀF =31.6Hz),129.5,126.2,126.1,124.4(q,J C ÀF =270.8Hz);HR-MS (ESI)m /z 240.0743[M +H]+,calcd for C 11H 9N 3F 3,240.0749.General Procedure for Organocatalytic Asymmetric Aza-Michael ÀMannich Reaction.To a solution of catalyst I (0.02mmol),benzoic acid (0.02mmol),and R ,β-unsaturated aldehyde 2(0.1mmol)in 0.3mL of DCM/MeOH (9/1)was added N -arylidene-1H -imidazol-2-amine 1(0.13mmol)at room temperature.After completion of the reaction as analyzed by TLC,the reaction mixture was directly purified by silica gel column chromatography to give the desired product 3.3was dissolved in 2mL of EtOH,and NaBH 4(1.0equiv)in EtOH (0.1M)was added.The mixture was stirred under room temperature for 30min.The volatile was evaporated under vacuum,and the residue was purified by silica gel column chromatography to give the corresponding alcohol 4in almost quantitative yield.(5S ,6S ,7R )-5,7-Diphenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3a).The title compound was ob-tained using the general procedure described above,in 80%yield and >99%ee:[R ]20D =+34.9(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.22(s,1H),7.49À7.46(m,2H),7.38À7.26(m,6H),7.20À7.15(m,2H),6.26(s,1H),6.01(s,1H),5.41(d,J =10.0Hz,1H),4.62(d,J =10.0Hz,1H),3.54À3.49(m,1H);13C NMR (125MHz,CDCl 3,ppm)δ200.1,148.3,138.0,137.4,129.0,128.9,128.85,128.7,127.7,127.5,123.6,112.6,60.4,57.9,57.3;HR-MS (ESI)m /z 336.1708[M +MeOH +H]+,calcd for C 20H 22N 3O 2,336.1712.The enantio-meric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =10.6min (major)and t r =32.5min (minor).(5S,6S,7R)-7-phenyl-5-m-tolyl-5,6,7,8-tetrahydroimidazo-[1,2-a]pyrimidine-6-carbaldehyde (3b).The title compound wasobtained using the general procedure described above,in 71%yield and 99%ee:[R ]20D =+38.3(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.24(d,J =1.2Hz,1H),7.50À7.48(m,2H),7.40À7.26(m,3H),7.22(dd,J =7.6,J =8.0Hz 1H),7.11(d,J =7.6Hz,1H),7.05À6.95(m,2H),6.35(s,1H),6.06(s,1H),5.38(d,J =10.4Hz,1H),4.62(d,J =10.4Hz,1H),3.54(ddd,J =1.2Hz,J =10.4Hz,J =10.4Hz,1H),2.31(s,3H);13C NMR (125MHz,CDCl 3,ppm)δ200.3,148.4,138.7,138.1,137.6,129.5,129.1,129.0,128.8,128.3,127.6,124.9,124.6,112.8,60.6,58.1,57.6,21.4;HR-MS (ESI)m /z 350.1866[M +MeOH +H]+,calcd for C 21H 24N 3O 2,350.1869.The enantio-meric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =8.5min (major)and t r =19.8min (minor).(5S ,6S ,7R )-5-(3-Methoxyphenyl)-7-phenyl-5,6,7,8-tetra-hydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3c).The ti-tle compound was obtained using the general procedure described above,in 50%yield and >99%ee:[R ]20D =+35.6(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.22(d,J =1.6Hz,1H),7.55À7.48(m,2H),7.46À7.30(m,3H),7.26À7.20(m,2H),6.85À6.78(m,2H),6.72(s,1H),6.29(s,1H),6.07(d,J =0.8Hz,1H),5.39(d,J =10.0Hz,1H),4.61(d,J =10.0Hz,1H),3.76(s,3H),3.52(ddd,J =1.6Hz,J =10.0Hz,J =10.0Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ200.2,159.9,148.4,139.7,137.6,129.9,129.03,129.0,127.5,124.6,120.0,114.1,113.2,112.7,60.5,58.0,57.6,55.3;HR-MS (ESI)m /z 366.1816Scheme 2.Proposed Catalytic Cycleofthe Domino Aza-Michael ÀMannich ReactionFigure 1.X-ray structure of 4n .[M+MeOH+H]+,calcd for C21H24N3O3,366.1818.The enantio-meric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4)using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/i-PrOH=9:1,flow rate=1.0mL/min:t r= 12.3min(major)and t r=28.3min(minor).(5S,6S,7R)-5-(3-Chlorophenyl)-7-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde(3d).The title com-pound was obtained using the general procedure described above,in60% yield and99%ee:[R]20D=+36.3(c=1.00in CH2Cl2);1H NMR(400 MHz,CDCl3,ppm)δ9.23(d,J=1.6Hz,1H),7.50À7.47(m,2H), 7.46À7.30(m,3H),7.30À7.20(m,2H),7.19(s,1H),7.12À7.08(m,1H), 6.50(d,J=1.6Hz,1H),6.10(d,J=1.6Hz,1H),5.89(br s,1H),5.46(d, J=10.0Hz,1H),4.61(d,J=10.0Hz,1H),3.50(ddd,J=1.6Hz,J=10.0 Hz,J=10.0Hz,1H);13C NMR(125MHz,CDCl3,ppm)δ199.6,148.2, 140.2,137.1,134.8,130.1,129.09,129.07,129.0,127.7,127.4,125.0,124.0, 112.6,60.1,57.2,57.0;HR-MS(ESI)m/z370.1323[M+MeOH+H]+, calcd for C20H21N3O2Cl,370.1322.The enantiomeric excess was deter-mined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4)using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/ i-PrOH=9:1,flow rate=1.0mL/min:t r=9.6min(major)and t r=37.8 min(minor).(5S,6S,7R)-5-(3-Bromophenyl)-7-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde(3e).The title com-pound was obtained using the general procedure described above,in 68%yield and>99%ee:[R]20D=+36.2(c=1.00in CH2Cl2);1H NMR (400MHz,CDCl3,ppm)δ9.23(d,J=1.2Hz,1H),7.50À7.45(m,2H), 7.42À7.26(m,5H),7.20À7.10(m,2H),6.21(s,1H),6.01(d,J=1.6Hz, 1H),5.42(d,J=9.6Hz,1H),4.58(d,J=10.0Hz,1H),3.48(ddd,J=1.2 Hz,J=9.6Hz,J=10.0Hz,1H);13C NMR(125MHz,CDCl3,ppm)δ199.8,148.6,140.9,137.4,131.8,130.6,130.4,129.1,129.0,127.5,126.4, 124.9,122.9,112.4,60.5,57.4,57.0;HR-MS(ESI)m/z414.0822[M+ MeOH+H]+,calcd for C20H21N3O2Br,414.0817.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH4)using a Daicel Chiralpak OD-H column, hexane(0.1%TEA)/i-PrOH=9:1,flow rate=1.0mL/min:t r=10.2min (major)and t r=37.5min(minor).(5S,6S,7R)-5-(3-Nitrophenyl)-7-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde(3f).The title com-pound was obtained using the general procedure described above, in70%yield and99%ee:[R]20D=+9(c=1.00in CH2Cl2);1H NMR(400MHz,CDCl3,ppm)δ9.27(d,J=0.8Hz,1H),8.13À8.11 (m,1H),8.01(s,1H),7.52À7.38(m,4H),7.38À7.26(m,3H),6.28 (d,J=1.2Hz,1H),6.00(d,J=1.6Hz,1H),5.64(d,J=8.8Hz,1H),4.68 (d,J=8.8Hz,1H),3.53À3.48(m,1H);13C NMR(125MHz,CDCl3, ppm)δ199.2,148.6,148.4,141.1,137.2,133.6,129.2,129.0,127.3, 125.3,123.5,122.5,112.2,60.1,57.0,56.4;HR-MS(ESI)m/z381.1559 [M+MeOH+H]+,calcd for C20H21N4O4,381.1563.The enantio-meric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4)using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/i-PrOH=85:15,flow rate=0.8mL/min: t r=15.8min(major)and t r=44.7min(minor).(5S,6S,7R)-7-Phenyl-5-p-tolyl-5,6,7,8-tetrahydroimidazo-[1,2-a]pyrimidine-6-carbaldehyde(3g).The title compound was obtained according to general procedure described above,in58%yield and99%ee:[R]20D=+44.8(c=1.00in CH2Cl2);1H NMR(400MHz, CDCl3,ppm)δ9.22(d,J=1.6Hz,1H),7.50À7.49(m,2H),7.48À7.26 (m,3H),7.20À7.05(m,4H),6.35(d,J=0.8Hz,1H),6.05(d,J=1.6 Hz,1H),5.38(d,J=10.0Hz,1H),4.61(d,J=10.4Hz,1H),3.52(ddd, J=1.6Hz,J=10.0Hz,J=10.4Hz,1H),2.32(s,3H);13C NMR(125 MHz,CDCl3,ppm)δ200.3,148.3,138.7,137.7,135.1,129.6,129.1, 129.0,127.7,127.6,124.6,112.7,60.7,57.9,57.7,21.1;HR-MS(ESI) m/z350.1869[M+MeOH+H]+,calcd for C21H24N3O2,350.1869. The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4)using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/i-PrOH=9:1,flow rate= 1.0mL/min:t r=9.7min(major)and t r=20.3min(minor).(5S,6S,7R)-5-(4-Methoxyphenyl)-7-phenyl-5,6,7,8-tetra-hydroimidazo[1,2-a]pyrimidine-6-carbaldehyde(3h).The title compound was obtained using the general procedure described above,in54%yield and>99%ee:[R]20D=+50.0(c=1.00in CH2Cl2); 1H NMR(400MHz,CDCl3,ppm)δ9.23(d,J=1.2Hz,1H), 7.51À7.48(m,2H),7.40À7.30(m,3H),7.13(d,J=8.4,Hz,2H), 6.84(d,J=8.4,Hz,2H),6.24(s,1H),6.02(s,1H),5.35(d,J=10.4Hz, 1H),4.60(d,J=10.0Hz,1H),3.78(s,3H),3.49(ddd,J=1.2Hz,J= 10.0Hz,J=10.4Hz,1H);13C NMR(125MHz,CDCl3,ppm)δ200.4, 159.7,148.5,137.7,130.0,129.0,128.9,127.6,124.4,114.2,112.4,60.7, 57.6,55.2;HR-MS(ESI)m/z366.1806[M+MeOH+H]+,calcd for C21H24N3O3,366.1818.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4)using a Daicel Chiralpak OD-H column,hexane(0.1% TEA)/i-PrOH=9:1,flow rate=1.0mL/min:t r=16.6min(major) and t r=33.5min(minor).(5S,6S,7R)-5-(4-Chlorophenyl)-7-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde(3i).The title com-pound was obtained according to general procedure described above,in 76%yield and98%ee:[R]20D=+47.8(c=1.00in CH2Cl2);1H NMR (400MHz,CDCl3,ppm)δ9.21(d,J=0.8Hz,1H),7.48À7.45(m,2H), 7.40À7.33(m,3H),7.29(d,J=8.4Hz,2H),7.13(d,J=8.4Hz,2H),6.38 (s,1H),6.04(s,1H),5.44(d,J=10.0Hz,1H),4.62(d,J=10.0Hz,1H), 3.49À3.44(m,1H);NMR(125MHz,CDCl3,ppm)δ199.7,148.1,137.0, 136.5,134.7,129.18,129.15,129.1,128.7,127.4,123.9,112.6,60.3,57.4, 57.1;HR-MS(ESI)m/z370.1316[M+MeOH+H]+,calcd for C20H21N3O2Cl,370.1322.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4) using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/i-PrOH= 9:1,flow rate=1.0mL/min:t r=11.0min(major)and t r=31.3min (minor).(5S,6S,7R)-5-(4-Bromophenyl)-7-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde(3j).The title com-pound was obtained using the general procedure described above,in 72%yield and98%ee:[R]20D=+64.4(c=1.00in CH2Cl2);1H NMR (400MHz,CDCl3,ppm)δ9.21(d,J=1.6Hz,1H),7.49À7.30(m,7H), 7.08(d,J=8.4Hz,2H),6.36(d,J=1.2Hz,1H),6.04(d,J=1.6Hz,1H), 5.43(d,J=10.0Hz,1H),4.59(d,J=10.0Hz,1H),3.47(ddd,J=1.6Hz, J=10.0Hz,J=10.0Hz,1H);13C NMR(125MHz,CDCl3,ppm)δ199.8,148.4,137.5,137.2,132.1,129.4,129.2,127.4,125.0,122.8,112.6, 60.7,57.6,57.2;HR-MS(ESI)m/z414.0809[M+MeOH+H]+,calcd for C20H21N3O2Br,414.0817.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4) using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/i-PrOH= 9:1,flow rate=1.0mL/min:t r=12.1min(major)and t r=35.2min (minor).(5S,6S,7R)-5-(4-Nitrophenyl)-7-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde(3k).The title com-pound was obtained using the general procedure described above,in 76%yield and>99%ee:[R]20D=+58.0(c=1.00in CH2Cl2);1H NMR(400MHz,CDCl3,ppm)δ9.25(d,J=0.8Hz,1H),8.11(d,J= 8.8Hz,1H),7.48À7.45(m,2H),7.39À7.26(m,5H),6.24(d,J= 1.6Hz,1H),5.99(d,J=1.6Hz,1H),5.63(d,J=9.2Hz,1H),4.63(d, J=9.2Hz,1H),3.45(ddd,J=0.8Hz,J=9.2Hz,J=9.2Hz,1H);13C NMR(125MHz,CDCl3,ppm)δ199.2,148.7,147.8,146.1,137.1, 129.2,129.1,128.6,127.3,125.3,124.0,112.3,60.3,57.4,56.5;HR-MS(ESI)m/z381.1554[M+MeOH+H]+,calcd for C20H21N4O4, 381.1563.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4) using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/i-PrOH= 80:20,flow rate=0.8mL/min:t r=14.3min(major)and t r=33.7min (minor).(5S ,6S ,7R )-5-(Benzo[d ][1,3]dioxol-5-yl)-7-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3l).Thetitle compound was obtained using the general procedure described above,in 66%yield and 99%ee:[R ]20D =+66.8(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.24(d,J =1.6Hz,1H),7.50À7.48(m,2H),7.42À7.28(m,3H),6.75À6.70(m,2H),6.65(s,1H),6.28(d,J =1.2Hz,1H),6.07(d,J =1.6Hz,1H),5.94(d,J =1.2Hz,2H),5.32(d,J =10.0Hz,1H),4.59(d,J =10.4Hz,1H),3.48(ddd,J =1.6Hz,J =10.0Hz,J =10.4Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ200.2,148.4,148.2,147.9,137.6,131.89,129.1,129.0,127.6,124.7,112.5,108.3,107.6,101.3,60.7,57.9,57.6;HR-MS (ESI)m /z 380.1597[M +MeOH +H]+,calcd for C 21H 22N 3O 4,380.1610.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =19.8min (major)and t r =33.9min (minor).(5S ,6S ,7R )-5-(Furan-2-yl)-7-phenyl-5,6,7,8-tetrahydroimi-dazo[1,2-a]pyrimidine-6-carbaldehyde (3m).The title com-pound was obtained using the general procedure described above,in 49%yield and 99%ee:[R ]20D =+52.3(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.34(d,J =1.2Hz,1H),7.49À7.45(m,2H),7.40À7.26(m,4H),6.33À6.28(m,3H),6.24(d,J =1.6Hz,1H),5.51(d,J =10.0Hz,1H),4.64(d,J =9.6Hz,1H),3.77(ddd,J =1.2Hz,J =9.6Hz,J =10.0Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ199.5,149.2,147.5,143.2,137.6,129.0,128.9,127.4,124.7,112.1,110.5,110.0,57.2,55.9,51.0;HR-MS (ESI)m /z 326.1499[M +MeOH +H]+,calcd for C 18H 20N 3O 3,326.1505.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =13.1min (major)and t r =40.5min (minor).(5S ,6S ,7R )-7-Phenyl-5-(thiophen-2-yl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde (3n).The title com-pound was obtained using the general procedure described above,in 42%yield and 99%ee:[R ]20D =+41.9(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.29(d,J =1.6Hz,1H),7.52À7.45(m,2H),7.42À7.32(m,3H),7.32À7.26(m,1H),7.05À7.04(m,1H),6.95À6.92(m,1H),6.30(d,J =1.6Hz,1H),6.20(d,J =1.6Hz,1H),5.72(d,J =10.4Hz,1H),4.60(d,J =10.0Hz,1H),3.61(ddd,J =1.2Hz,J =10.0Hz,J =10.4Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ199.8,147.8,140.6,137.4,129.1,127.9,127.6,126.8,126.5,124.7,112.4,60.7,57.8,53.6;HR-MS (ESI)m /z 342.1263[M +MeOH +H]+,calcd for C 18H 20N 3O 2S,342.1276.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =12.7min (major)and t r =27.0min (minor).(5S ,6S ,7R )-5-(4-Chlorophenyl)-7-(4-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3o).The title compound was obtained using the general procedure de-scribed above,in 60%yield and 98%ee:[R ]20D =+28.6(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.22(d,J =1.6Hz,1H),7.39(d,J =8.8Hz,2H),7.30(d,J =8.4Hz,2H),7.15(d,J =8.8Hz,2H),6.91(d,J =8.8Hz,2H),6.38(d,J =1.6Hz,1H),6.03(d,J =1.2Hz,1H),5.43(d,J =10Hz,1H),4.54(d,J =10.0Hz,1H),3.80(s,3H),3.43(ddd,J =1.6Hz,J =10.0Hz,J =10.0Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ200.0,160.1,148.5,137.0,134.6,129.1,128.6,125.1,114.5,112.6,60.9,57.2,57.1,55.3;HR-MS (ESI)m /z 400.1422[M +MeOH +H]+,calcd for C 21H 23N 3O 3Cl,400.1428.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =20.3min (major)and t r =47.0min (minor).(5S ,6S ,7R )-7-(4-Methoxyphenyl)-5-(4-nitrophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3p).The title compound was obtained using the general procedure described above,in 62%yield and 97%ee:[R ]20D =+57.4(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.23(d,J =0.8Hz,1H),8.15(d,J =8.8Hz,2H),7.39(d,J =8.8Hz,2H),7.34(d,J =8.8Hz,2H),6.89(d,J =8.8Hz,2H),6.31(d,J =1.6Hz,1H),5.99(d,J =1.2Hz,1H),5.62(d,J =9.6Hz,1H),4.57(d,J =9.6Hz,1H),3.79(s,3H),3.44(ddd,J =0.8Hz,J =9.6Hz,J =9.6Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ199.4,160.2,148.8,146.1,128.8,128.7,128.5,125.4,124.0,114.5,112.3,60.7,56.8,56.6,55.3;HR-MS (ESI)m /z 411.1656[M +MeOH +H]+,calcd for C 21H 23N 4O 5,411.1668.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =80:20,flow rate =0.8mL/min:t r =19.7min (major)and t r =40.0min (minor).(5S ,6S ,7R )-5-Phenyl-7-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3q).The title compound was obtained using the general procedure described above,in 85%yield and 99%ee:[R ]20D =+13.7(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.29(d,J =1.6Hz,1H),7.62À7.60(m,4H),7.32À7.26(m,3H),7.17À7.14(m,2H),6.19(d,J =1.6Hz,1H),6.05(d,J =1.2Hz,1H),5.41(d,J =9.6Hz,1H),4.77(d,J =9.6Hz,1H),3.53(ddd,J =1.2Hz,J =9.6Hz,J =9.6Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ199.7,148.2,142.0,137.7,131.0(q,J C ÀF =32.5Hz),129.0,128.9,128.0,127.5,127.0,125.9,125.8,124.4,123.8(q,J C ÀF =271.0Hz),112.7,60.2,58.0,56.7;HR-MS (ESI)m /z 404.1569[M +MeOH +H]+,calcd for C 21H 21F 3N 3O 2,404.1586.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =8.00min (major)and t r =33.2min (minor).(5S ,6S ,7R )-5-Phenyl-7-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3r).The title compound was obtained using the general procedure described above,in 87%yield and 99%ee:[R ]20D =+21.1(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.28(d,J =1.6Hz,1H),7.62(dd,J =8.4Hz,J =8.4Hz,4H),7.28(d,J =8.4Hz,2H),7.10(d,J =8.4Hz,2H),6.25(d,J =1.6Hz,1H),6.05(d,J =1.6Hz,1H),5.44(d,J =9.6Hz,1H),4.74(d,J =9.6Hz,1H),3.47(ddd,J =1.6Hz,J =9.6Hz,J =9.6Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ199.3,148.1,141.7,136.3,134.8,131.2(q,J C ÀF =36.3Hz),129.0,128.9,128.9,127.9,127.0,124.8,123.7(q,J C ÀF =276.0Hz),112.6,60.2,57.2,56.7;HR-MS (ESI)m /z 438.1192[M +MeOH +H]+,calcd for C 21H 20ClF 3N 3O 2,438.1196.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =9.00min (major)and t r =30.7min (minor).(5S ,6S ,7R )-5-Phenyl-7-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3s).The title compound was obtained using the general procedure described above,in 75%yield and 99%ee:[R ]20D =+33.0(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.29(d,J =1.2Hz,1H),8.16(d,J =8.4Hz,2H),7.62(dd,J =8.4Hz,J =8.4Hz,4H),7.33(d,J =8.8Hz,2H),6.53(d,J =1.6Hz,1H),6.11(d,J =1.6Hz,1H),5.68(d,J =9.2Hz,1H),4.79(d,J =9.2Hz,1H),3.50(ddd,J =1.2Hz,J =9.2Hz,J =9.2Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ198.5,148.2,147.9,145.4,141.4,131.3(q,J C ÀF =32.5Hz),128.4,127.8,126.1,126.0,125.1,124.7,123.3(q,J C ÀF =270.0Hz),112.5,59.8,56.4,56.3;HR-MS (ESI)m /z 449.1422[M +MeOH +H]+,calcd for C 21H 20F 3N 4O 4,449.1437.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =80:20,flow rate =0.8mL/min:t r =12.7min (major)and t r =26.1min (minor).。

曼尼希反应曼尼希反应（中国海洋大学化学化工学院，中国青岛，266100）摘要：本文简单的概述了曼尼希反应的发现历史，反应的机理，在合成中的应用，以及对各个领域发展趋势进行了探讨曼尼希反应的发现，以及后期对其进入的深入研究，在有机化学中逐渐奠定了曼尼希反应的基础。

很多生物碱都是通过曼尼希反应合成的，它具有很强的反应性，可以使很多在通常条件下难以进行的反应得以顺利进行。

对其反应的研究有助于我们更好的将其应用于实际中关键词：曼尼希反应；机理；应用曼尼希反应（Mannich反应，简称曼氏反应），也称作胺甲基化反应，是含有活泼氢的化合物（通常为羰基化合物）与甲醛和二级胺或氨缩合，生成β-氨基（羰基）化合物的有机化学反应。

1.曼尼希反应的历史曼尼希是从1917年开始系统研究胺甲基化这类反应的，并发现了它的普遍意义，然而早在1895年便有人发现以酚作酸组分的曼尼希碱，并申请了专利。

之后，Tollens、L. Henry、Duden、Franchimont等人发现了其他类型的曼尼希反应，包括以硝基烷和伯硝胺作酸组分的反应，但都没有意识到这些反应所具有的普遍意义。

1912年，卡尔·曼尼希用沙利比林和乌洛托品反应，得到了一个难溶于水的沉淀。

此产物的结构在一年内得到了解释，促使了他对这一类含活泼氢化合物、甲醛和胺之间的反应进行了深入的研究，从而奠定了曼尼希反应的基础。

很多生物碱都是通过曼尼希反应合成的。

1917年曼尼希发现胺类盐酸盐、甲醛与C—H酸化合物，特别是酮的反应，不仅能够制备酮碱，而且，适当选择反应组分，还能制备出类似生物碱特性的物质。

托品酮的合成是曼尼希反应的经典例子，被认为是全合成中的经典反应之一。

1901年，Willstätter首先合成了这个化合物，用的是环庚酮作原料，通过14步反应，总产率仅为0.75%。

1917年，罗伯特·鲁宾逊以丁二醛、甲胺和3-氧代戊二酸为原料，在仿生条件下，利用了曼尼希反应，仅通过一步反应便得到了托品酮。

mannich(曼尼希)反应芳伯氨基曼尼希反应（Mannich Reaction）是一种重要的有机合成方法，通常用于合成含有氨基取代基的化合物。

它是Carl Mannich在1912年首次描述的，因此得名曼尼希反应。

曼尼希反应的产物通常是含有芳香性的氨基取代基的化合物。

曼尼希反应主要通过亲核加成的方式进行。

在反应中，一个缺电子的亲电体与两个充当亲核试剂的化合物发生反应，生成一个氨基取代的产物。

一般来说，亲电体是一个含有碳酰基、羰基或亚环的化合物，而亲核试剂则是含有胺基或胺类衍生物的化合物。

曼尼希反应的基本机理如下：1. 亲电体的酸质子（H+）被亲核试剂中的胺基、氨基或氧化胺等亲核试剂攻击，形成一个带正电荷的中间体。

2. 亲电体中的羰基与亲核试剂中的亲核试剂之间发生亲核加成反应，生成一个含有酰胺结构的中间体。

3. 中间体内部发生质子转移，使反应系统趋向于更稳定的状态，形成最终产物。

曼尼希反应的应用广泛，可以用于合成各种含有氨基取代基的有机化合物。

例如，通过曼尼希反应可以将芳香酮与胺类化合物反应，合成相应的酰胺。

此外，曼尼希反应还可用于构建含有多个官能团的复杂有机化合物。

除了简单的酰胺合成外，曼尼希反应也可以用于合成深色芳香胺化合物。

例如，在色素合成中，曼尼希反应是合成含有芳香胺基团的重要方法之一。

曼尼希反应还可以用于制备药物和天然产物的合成，具有重要的应用价值。

曼尼希反应在实验室中的条件通常是在温和的酸性条件下进行。

常用的催化剂包括各种酸，如HCl、H2SO4、三氟甲磺酸等。

此外，一些碱性条件下也可以进行曼尼希反应。

总结来说，曼尼希反应是一种重要的有机合成方法，通常用于合成含有氨基取代基的化合物。

它的机理简单，应用广泛，可以用于合成各种复杂的有机化合物。

曼尼希反应在合成药物、天然产物和色素等领域有着重要的应用价值。

分子内的曼尼希反应
曼尼希反应是一种重要的有机化学反应，可以用于合成氨基酸、药物、香料等有机分子。

该反应发生在分子内部，通常需要在酸性条件下进行。

曼尼希反应的机理涉及两个关键步骤：1）亲电性基团攻击羧基
产生酰氨中间体；2）中间体内部的质子转移和脱水反应形成香豆酸
衍生物。

这两个步骤都需要酸性条件的催化。

曼尼希反应可以应用于不同类型的化合物，如酰胺、酮、酯等。

此外，该反应还可以与其他反应如氧化、还原、烷基化等反应组合使用，形成复杂的分子结构。

因此，曼尼希反应是有机合成中的重要反应之一。

最近的研究表明，曼尼希反应还可以在生物合成中发挥重要作用。

这一发现为生物化学研究提供了新的方向，也为有机合成的发展提供了新的思路。

- 1 -。

曼尼希反应曼尼希反应（Mannich反应，简称曼氏反应），也称作胺甲基化反应，是含有活泼氢的化合物（通常为羰基化合物）与甲醛和二级胺或氨缩合，生成β-氨基（羰基）化合物的有机化学反应。

一般醛亚胺与α-亚甲基羰基化合物的反应也被看做曼尼希反应。

反应的产物β-氨基（羰基）化合物称为“曼尼希碱”（Mannich碱），简称曼氏碱。

反应中的胺一般为二级胺，如哌啶、二甲胺等。

如果用一级胺，反应后的缩合产物在氮上还有氢，可以继续发生反应，故有时也可根据需要使用一级胺。

如果用三级胺或芳香胺，反应中无法生成亚胺离子，停留在季铵离子一步。

胺／氨的作用是活化另一个反应物醛。

甲醛是最常用的醛，一般用它的水溶液、三聚甲醛或多聚甲醛。

除甲醛外，也可用其他醛。

反应一般在水、乙酸或醇中进行，加入少量盐酸以保证酸性。

含α-氢的化合物一般为羰基化合物（醛、酮、羧酸、酯）、腈、脂肪硝基化合物、末端炔烃、α-烷基吡啶或亚胺等。

若用不对称的酮，则产物是混合物。

呋喃、吡咯、噻吩等杂环化合物也可反应。

曼氏反应通常需在高温下和质子溶剂中进行，反应时间长，容易生成副产物。

反应的机理如下图所示。

羰基质子化，胺对羰基发生亲核加成，去质子，氮上的电子转移，水离去，可以得到一个亚胺离子中间体。

以二甲胺作原料，这个中间体为N,N-二甲基-亚甲基氯化铵，在70年代由Kinact等人首先发现。

它具有很强的反应性，可以使很多在通常条件下难以进行的反应得以顺利进行。

亚胺离子作为亲电试剂，进攻含活泼氢化合物的烯醇型结构，失去质子，便得到产物。

产物曼氏碱比较稳定，以它作原料，经甲基化与Hofmann消除反应，或在蒸馏时和碱作用下发生的分解反应，可以得到α,β-不饱和酮。

后者可以与亲核试剂发生麦克尔加成等反应，是很有用的合成前体，但由于它一般不稳定，容易聚合，故通常采用曼氏碱分解生成不饱和酮，并使其在原位与其它试剂发生反应。

【中文名称】双氰胺；氰基胺；二氰二氨；氰基胍，二聚氰胺，二聚氨基氰，氰胍【英文名称】dicyandiamide;cyanoguanidine；cyano-Guanidine；Dicyandiamide 【英文缩写】DICY；Dicy 【CAS No】 461-58-5 【结构或分子式】C2H4N4 【相对分子量或原子量】84.08 【密度】1.404；1.400（25℃）【熔点（℃）】208～212 【毒性LD50(mg/kg)】小鼠经口12000。

曼尼希反应及其不对称合成有⼈曾今说过这句名⾔：“宇宙是不对称的，⽣命世界也是不对称的。

”诚然，⾃然界往往⼤量存在物质的其中⼀种⼿性异构体，例如⾃然界中存在的氨基酸为L-构型，⽽蛋⽩质与DNA⼜都是右旋的螺旋构象。

虽然从分⼦式上看，这些物质⼀模⼀样，化学性质也⼏乎没有差别，但其空间结构存在差异，构成了实物与镜像的关系，不能重叠。

令⼈类惊醒的是，这些被称为对映异构体的药物等化合物的异构体往往表现出不同甚⾄相反的⽣物活性。

因⽽，从事化学制药需要克服的⼀个困难之⼀就是如何获得对映体纯的化合物。

要想获得对映体纯的化合物，就离不开不对称有机合成。

随着科学的不断发展，不对称有机反应在测定⼿性化合物的相对和绝对构型以及制备光学活性有机化合物等⽅⾯都发挥了⾮常重要的作⽤，尤其是在制药⼯业⽅⾯。

由于不对称有机反应的迅速发展，使得越来越多的药物得到更多的制备。

其中β-氨基酸衍⽣物是药物中间体的重要组成部分，然⽽⼤部分都不是天然就有的。

因此，不对称的Mannich反应是合成光学β-氨基酸及其衍⽣物的重要⽅法之⼀。

下⾯介绍满Mannich反应历史及其不对称合成。

Mannich反应的历史及其反应机理在⼤约19世纪末的时候就有⼈利⽤了以酚作酸组分的曼尼希碱，并且申请了专利。

之后，Tollens、L.Henry等⼈发现了其他类型的曼尼希反应，包括以硝基烷和伯硝胺作酸组分的反应，但均没有意识到其重要意义。

直到1912年，曼尼⼣⽤沙利⽐林和乌洛托品反应，得到⼀个难溶于⽔的沉淀。

此产物的结构在⼀年之内得到了解释，促使他对这⼀类含活泼氢化合物、甲醛和胺之间的反应进⾏了深⼊的研究，从⽽奠定了曼尼⼣反应的基础。

说到曼尼⼣，就不得不提⼀下托品酮。

托品酮的合成是曼尼⼣反应最经典的例⼦。

托品酮最早的全合成是由德国化学家Willstatter在1902年完成的。

这是⼀项很优秀，很杰出的⼯作，也是当时合成化学的典范。

因此，他在1915年获得了诺贝尔化学奖。

曼尼希反应
定义：
曼尼希反应是一种三组分缩合反应，涉及醛或酮、氨基化合物和甲醛的反应，生成β-羟基胺。

反应机理：
1.氨基化合物与甲醛反应，生成亚胺（即席夫碱）。

2.醛或酮亲核加成到亚胺上，形成季铵盐中间体。

3.季铵盐中间体消除甲醇，产生β-羟基胺。

用途：
•合成β-羟基胺和β-氨基酮
•制备药物、天然产物和聚合物
席夫碱反应
定义：
席夫碱反应是一种醛或酮与伯胺或仲胺反应，生成席夫碱（也称为亚胺）的反应。

反应机理：
1.胺的氮原子亲核加成到醛或酮的羰基碳上。

2.消除水分子，生成席夫碱。

用途：
•检测醛或酮的存在（2,4-二硝基苯肼法）
•合成染料、药物和聚合物
•作为配体，与金属离子形成配合物
曼尼希反应和席夫碱反应的比较
特征曼尼希反应席夫碱反应
反应类型三组分缩合二组分缩合
反应物醛或酮、氨基化合物、甲醛醛或酮、伯胺或仲胺
产物β-羟基胺席夫碱（亚胺）
反应机理涉及季铵盐中间体涉及水分子消除
用途合成β-羟基胺和β-氨基酮合成染料、药物和聚合物。

曼尼希反应和席夫碱反应
曼尼希反应和席夫碱反应是有机化学中常见的两种反应，分别用于合成不同类型的化合物。

下面将分别介绍这两种反应的原理、机理和应用。

曼尼希反应是一种重要的有机合成反应，通常用于合成醛和酮。

该反应的机理是通过氧化芳香烃来生成醛和酮。

反应的催化剂通常是金属氧化物或过渡金属盐。

在反应中，芳香烃首先被氧化为芳香醇，然后再被氧化为醛或酮。

曼尼希反应可以用于合成各种醛和酮，具有较好的反应选择性和产率，因此在有机合成中得到广泛应用。

席夫碱反应是一种经典的有机反应，常用于合成醛和酮。

反应的原理是通过芳香胺和醛或酮的反应生成席夫碱。

席夫碱反应是一种亲核加成反应，通常在碱性条件下进行。

反应的机理是首先芳香胺和醛或酮发生亲核加成反应生成中间体，然后中间体经过脱水反应生成席夫碱。

席夫碱反应是一种重要的合成方法，可以合成各种席夫碱衍生物，具有较好的反应活性和反应条件选择性。

总的来说，曼尼希反应和席夫碱反应是有机化学中常用的两种反应，分别用于合成醛和酮以及席夫碱。

通过深入了解这两种反应的原理、机理和应用，可以更好地应用它们进行有机合成，为化学研究和工业应用提供帮助。

曼尼希反应详细资料大全曼尼希反应（Mannich反应，简称曼氏反应），也称作胺甲基化反应，是含有活泼氢的化合物（通常为羰基化合物）与甲醛和二级胺或氨缩合，生成β-氨基（羰基）化合物的有机化学反应。

一般醛亚胺与α-亚甲基羰基化合物的反应也被看做曼尼希反应。

反应的产物β-氨基（羰基）化合物称为“曼尼希碱”（Mannich碱），简称曼氏碱。

基本介绍•中文名：曼尼希反应（•外文名：Mannich反应•别称：曼氏反应•套用学科：有机化学•适用领域范围：化工生产•反应机理：胺对羰基发生亲核加成•：概述,反应机理,发展历史,套用,反应的立体选择性,概述反应中的胺一般为二级胺，如哌啶、二甲胺等。

如果用一级胺，反应后的缩合产物在氮上还有氢，可以继续发生反应，故有时也可根据需要使用一级胺，一级胺与甲醛常温下会迅速脱水，形成希夫碱。

如果用三级胺或芳香胺，反应中无法生成亚胺离子，停留在季铵离子一步。

胺/氨的作用是活化另一个反应物醛。

甲醛是最常用的醛，一般用它的水溶液、三聚甲醛或多聚甲醛。

除甲醛外，也可用其他醛。

反应一般在水、乙酸或醇中进行，加入少量盐酸以保证酸性。

含α-氢的化合物一般为羰基化合物（醛、酮、羧酸、酯）、腈、脂肪硝基化合物、末端炔烃、α-烷基吡啶或亚胺等。

若用不对称的酮，则产物是混合物。

呋喃、吡咯、噻吩等杂环化合物也可反应。

曼氏反应通常需在高温下和质子溶剂中进行，反应时间长，容易生成副产物。

反应机理反应的机理如下图所示。

羰基质子化，胺对羰基发生亲核加成，去质子，氮上的电子转移，水离去，可以得到一个亚胺离子中间体。

以二甲胺作原料，这个中间体为N, N-二甲基-亚甲基氯化铵，在70年代由Kinact等人首先发现。

它具有很强的反应性，可以使很多在通常条件下难以进行的反应得以顺利进行。

反应机理亚胺离子作为亲电试剂，进攻含活泼氢化合物的烯醇型结构，失去质子，便得到产物。

产物曼氏碱比较稳定，以它作原料，经甲基化与Hofmann消除反应，或在蒸馏时和碱作用下发生的分解反应，可以得到α,β-不饱和酮。