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第一节a-羟烷基、卤烷基、氨烷基化反应一、a-羟烷基化反应1.醇醛缩合反应(Aldol缩合)(1)含有a-活泼氢的醛或酮的自身缩合
1碱催化机理:
2
3甲醛与含有a-活泼氢的醛、酮之间的缩合三羟甲基丙烷
4催化剂的影响以碱催化剂为主,酸催化剂应用较少④应用特点定向醇、醛缩合(a)烯醇盐法
5(b)烯醇硅醚法
6(2)芳醛与a-活性氢的醛、酮的缩合
7应用特点制备反式芳丙醛
8有机小分子脯氨酸催化直接Aldol反应List,B.etal,J.Am.Chem.Soc.2000,122,2395制备手性b-羟基醛
9
10(3)分子内的羟醛缩合
11Robinson环化
12
13
14
15
162.不饱和烃的a羟烷基化(Prins反应)
17
18Mechanism
19
20
213.安息香缩合
22
23影响因素①芳醛结构的影响强吸电子、强供电子对反应都不利;自身缩合、交叉缩合
24②催化剂的影响NaCN剧毒,可用噻唑鎓盐、咪唑鎓盐等代替
25
26
27Example
28
294.有机金属化合物的a-羟烷基化(1)Reformatsky反应:醛或酮与a-卤代酸酯在金属锌粉存在下缩合而得b-羟基酸酯或脱水得a、b-不饱和羧酸酯的反应:
30
31metal:Zn,Mg,Cd,Ba,In,Ge,Co,Ni,Ce;metalsalt:SmI2,CrCl2,TiCl2,CeX3,Na2Te,R3SnLi,R3Sb/I2,Et2AlCl
32mostoftenethersolventsareusedsuchasdiethylether,tetrahydrofuran,1,4-dioxaneanddimethoxyethane,butmixturesofthesesolventswitharomatichydrocarbonsandmorepolarsolventssuchasacetonitrile,dimethylformamide,dimethylsulphoxide,andhexamethylphosphorictriamidearealsoused;
33
34催化剂锌粉必须活化,常用20%盐酸处理,再用丙酮、乙醚洗涤,真空干燥。亦可用K、Na、Li等还原无水氯化锌,此法活性较高。Mg,Cd,Ba,In,Ge,Co,Ni,Ce等。
35例如:加入(CH3O)3B/THF可提高收率(如上)
36(2)Grignard反应
37
38
39机理:
40
41③影响因素1)thereagentsarepredominantlypreparedbyreactingalkyl,aryl,orvinylhalideswithmagnesiummetalinaproticnucleophilicsolvents(e.g.,ethers,tertiaryamines);2)thereagentsareusuallythermodynamicallystablebutairandmoisturesensitiveandincompatiblewithacidicfunctionalgroups(e.g.,alcohols,thiols,phenols,carboxylicacids,1°,2°amines,terminalalkynes);
42二、a-卤烷基化反应(Blanc反应)
433.影响因素也可用ZnCl2(干)等Lewis酸。苯环上供电子基,有利于反应进行。吸电子基不利于反应进行。(87%)
44引入-CH2Cl后,可进一步转化成其他官能团并增长碳链。
45三、a-氨烷基化反应Mannich反应:有活泼氢的化合物(醛、酮等)与甲醛、胺进行缩合,H原子被a-氨甲基取代称为a-氨甲基化反应(Mannich反应)
46反应机理
47
48如:(90%)抗胆碱药阿托品的中间体
49Introduction
501.MetalCatalysis2.ProlineCatalysis3.BrønstedAcid-Catalysis4.ProtonatedChiralCatalysis5.ACDC6.H-BondCatalysis7.PTC
51Trost,B.M.J.Am.Chem.Soc.2006,128,2778-2779.
52Prolinecatalysis
53Brønstedacid-catalysis磷原子的四齿结构(2)磷酸的酸性足以诱捕亚胺(3)双功能手性催化剂
544.ProtonatedChiralCatalysisJ.Am.Chem.Soc.2004,126,3418-3419
55Ishihara,K.J.Am.Chem.Soc2008,130,16858–16860.
56H-BondCatalysis
57Jacobsen,E.N.Angew.Chem.Int.Ed.2005,44,466–468.
582.Pictet-Spenglerreaction
59
60Baldwin环化规则
61Baldwin环化规则SP3=tet;SP2=trig;SP=digSP3:5-6-endo禁阻SP2:3-5-endo禁阻SP:3-4-exo禁阻其他允许
62(3)影响因素①onlyβ-arylethylamineswithelectron-donatingsubstituentsaffordhighyields;②thereactionisusuallycarriedoutwithaslightexcessofthecarbonylcompound(toensurethecompleteconsumptionoftheamine)ineitherproticoraproticmedium;
633.Strecker反应(1)反应通式
64(2)反应机理
65(3)应用-Corey,1999
66第三节b-羟烷基、b-羰烷基化反应一b-羟烷基化反应1.反应通式-F-C反应
672.反应机理
68苯环连在取代基多的C上3.应用特点(1)区域选择性
69(2)立体选择性构型反转
70(3)制备环内酯
71二、b-羰烷基化反应Michael加成反应
72
73反应机理:
74
75(3)影响因素1)thenucleophile(Michaeldonor)canbederivedbythedeprotonationofCH-activatedcompoundssuchasaldehydes,ketones,nitriles,β-dicarbonylcompounds,etc.aswellasbythedeprotonationofheteroatoms;
762)dependingonthetypeandstrengthoftheelectron-withdrawinggroup(negativechargestabilizinggroup),theuseofevenrelativelyweakbasesispossible(e.g.,NEt3);
77(4)应用
78第四节亚甲基化反应一羰基烯化反应(1)反应通式及机理
79
80(2)影响因素
81theylidesarewateraswellasoxygen-sensitive;thephosphorousylideschemoselectivelyreactwithaldehydes(fast)andketones(slow),othercarbonylgroups(e.g.,esters,amides)remainintactduringthereaction;thestereoselectivity,E-orZ-selectivity,isinfluencedbymanyfactors:typeofylide,typeofcarbonylcompound,natureofsolvent;
82TheWittigreactionhasseveralimportantvariants:HWEReaction
83①thephosphonatecarbanionsaremorenucleophilicthanthecorrespondingphosphorousylides,sotheyreadilyreactwithpracticallyallaldehydesandketonesundermilderreactionconditions;②theby-productdialkylphosphatesarewater-soluble,soitismucheasiertoseparatethemfromthealkeneproductsthanfromthewater-insolubletriphenylphosphineoxide.
84③high(E)-selectivityfordisubstitutedalkenesundermuchmilderconditionsthannormallyusedinWittigreactions;④the(E)-selectivityismaximizedbyincreasingthesizeofthealkylgroupoftheR1orR2substituents
85⑤ThereareanimportantmodificationsoftheHWEolefination:intheStill-GennarimodificationR1=OCH2CF3andthereactionaffords(Z)-olefinsexclusively;forbase-sensitivesubstrates,theuseofametalsalt(LiClorNaI)andaweakaminebase(e.g.,DBU)hasproveneffectivetoavoidepimerization.
86(4)应用
87
88二羰基a位的亚甲基化反应活性亚甲基的亚甲基化Knoevenagel反应(1)反应通式
89
90(2)反应机理
91
92(3)影响因素①thenatureofthecatalystisimportant,usuallyprimary,secondary,andtertiaryaminesandtheircorrespondingammoniumsalts,certainLewisacidscombinedwithatertiaryamine(e.g.,TiCl4/Et3N).
93②theby-productofthereactioniswateranditsremovalfromthereactionmixturebymeansofazeotropicdistillation,theadditionofmolecularsieves,orotherdehydratingagentsshiftstheequilibriumtowardtheformationoftheproduct;
94③thechoiceofsolventiscrucialandtheuseofdipolaraproticsolvents(e.g.,DMF)isadvantageous,sinceproticsolventsinhibitthelast1,2-eliminationstep;
952.Stobbe反应(1)反应通式
96(2)反应机理
97
98(3)应用制备烯酸
99
1003.Perkin反应(1)反应通式
101(2)反应机理
102
103(3)影响因素①芳香醛结构影响吸电子活性增强,给电子相反
104碘番酸中间体
105②催化剂的影响相应羧酸的钾盐、钠盐;铯盐效果更好
106(4)应用
107
108第五节a、b-环氧烷基化反应(Darzens反应)1.反应通式EWG=CO2R,CN,SO2R,CONR2,C(=O),C(=NR);Y=O,NR;
1092.反应机理
1103.影响因素Aliphaticaldehydesusuallygiveloweryields;α-Chloroestersarepreferabletobromooriodoesters,sincetheygivehigheryields;α-halosulfones,nitriles,ketones,ketimines,thiolesters,oramides,canalsobeusedtoobtainthecorrespondingderivatives;
1114.应用特点
112醛、酮同系化C+1
113布洛芬的合成
114第六节环加成反应EDG(electron-donatinggroup)=alkyl,O-alkyl,N-alkyl,etc.EWG(electron-withdrawinggroup)=CN,NO2,CHO,COR,COAr,CO2H,CO2R,COCletc.一、D-A反应
115
116
117Mechanism
118(3)影响因素及应用特点①共轭二烯双键必需是顺型的②顺式原理
119③内向加成原理
120④加成定位规则
121Example
122
123二、1,3偶极环加成1.AzomethineYlides
124
1252.AzomethineImines3.Nitrones
1264.Azides
1275.O3/CarbonylOxides
128三、碳烯、氮烯对不饱和键的加成Carbene-电中性二价碳中间体,两电子自选方向相同为三线态,相反为单线态
129单线态与烯烃的反应有立体定向性三线态与烯烃的反应不具有立体定向性
130Simmons-Smithcyclopropanation.
131
132
133(1)awiderangeofalkenescanbeused:simplealkenes,α,β-unsaturatesketonesandaldehydes,electronrichalkenes;(2)duetotheelectrophilicnatureofthereagent,therateofcyclopropanationisfasterwithmoreelectronrichalkenes.However,highlysubstitutedalkenesmayreactslowerduetotheincreasedsterichindrance;
134(3)thecyclopropanationisstereospecific,sothestereochemicalinformationinthealkenesubstratesistranslatedtotheproducts;(4)whenthealkenehasfunctionalgroupscontainingheteroatoms(e.g.,OH,OAc,OMe,OBn,NHR),astrongdirectingeffectisobservedandthedeliveryofthealkylideneoccursfromthefaceofthedoublebondhavingthecloserproximityofthefunctionalgroup;
135Example
136
137习题:P164第一题