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Chapter 2. Addition to Carbonyl Groups
Advanced Org Chem-Carey B Fall 2008 Chapter 2. Addition to Carbonyl Groups CareyB-Chap2-5ed Chapter 2-5ed
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Enolates Addition to Carbonyl Groups
Advanced Org Chem-Carey B Fall 2008 Enolates Addition to Carbonyl Groups CareyB-Chap2-5ed Chapter 2-5ed
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Aldol Addition & Condensation Reactions
Advanced Org Chem-Carey B Fall 2008 Aldol Addition & Condensation Reactions General mechanism: base-/acid-catalyzed Directed aldol reactions: regio-/stereospecific control of enolate stereochemistry: diastereoselectivity greater E with LiBr: larger aggregation; 68 middle mechanism of aldol addition: cyclic chair-like TS chelating atoms: Zimmerman-Traxler model; 68 top greater selectivity with Z-enolates: 69 top & 70 Table 2.1 alternative transition-state models for aldol reactions cyclic ketones: only E-enolates; 69 middle more stable anti: by equilibration; 71 middle CareyB-Chap2-5ed Chapter 2-5ed
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Diastereoselective Aldol Reactions
Advanced Org Chem-Carey B Fall 2008 Diastereoselective Aldol Reactions Generalizations Z-enolates to syn & E-enolates to anti aldol products better selectivities when R1 or R3 is large reversed correlation when R2 is very large CareyB-Chap2-5ed Chapter 2-5ed
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Alternative Models (III): Open TS
Advanced Org Chem-Carey B Fall 2008 Alternative Models (III): Open TS Noyori JACS 1977, 99, 1265 & 1981, 103, 2106 syn aldols irrespective of the enolate geometry CareyB-Chap2-5ed Chapter 2-5ed
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Advanced Org Chem-Carey B
Fall 2008 Boron Enolates Higher selectivity: cyclic chair TS; 72 top more compact TS larger steric interaction: B-O Å; Li-O Å; Mg-O Å; B > Li > Na > K 74 Table 2.2; however, often lower selectivity with E-enolates Stereoselective preparation: Z- vs E-enolate deprotonation with R2B-X & 3o amines: 73 top factors for E & Z: R2B-X & 3o amines, size of R1 & R2 Z-enolates: equilibrated boronation of silyl ethers; 73 middle highly stereoselective enolate preparation: ketones, esters no further chelation to intramolecular electron donor atoms CareyB-Chap2-5ed Chapter 2-5ed
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Formation of Z-enolates: Equilibration
Advanced Org Chem-Carey B Fall 2008 Formation of Z-enolates: Equilibration CareyB-Chap2-5ed Chapter 2-5ed
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Other Metal Enolates: Ti, Sn, Zr
Advanced Org Chem-Carey B Fall 2008 Other Metal Enolates: Ti, Sn, Zr Ti enolates: chair TS & stronger chelation; 74 bot unsymmetrical ketones: more substituted; 75 middle aldehyde & ‘ate’ complexes: more reactive; 75 top & bot Sn (II) enolates: syn selective; 76 middle good reactivity with ketones: 76 bottom aldol reactions with R3Sn enolates: chair TS; 77 top Zr enolates: Cp2ZrCl2 & R3N / Zr(OtBu)4; 77 bottom cyclic TS but less selective: B > Zr > Li; 78 top CareyB-Chap2-5ed Chapter 2-5ed
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Lewis Acid-Catalyzed Aldol Additions
Advanced Org Chem-Carey B Fall 2008 Lewis Acid-Catalyzed Aldol Additions Mukaiyama reaction: silyl enol ethers & BF3; 82 top open TS: dependent on the size of R1; 82 bottom other Lewis acids: Ti/SnCl4, Cp2Ti(OTf)2, R2Sn(OTf)2, Sn/Zn(OTf)2, R3SiOTf-B(OTf)3 or (ArO)2AlR, R3SnClO4, Ph3CClO4 TMSi+: active catalyst; 83 middle & 84 top cat. Yb(OTf)3 in aqueous solvent: affinity to C=O; 84 middle InCl3: faster ligand exchange & proper acidity; 84 bottom acetals as electrophiles: b-alkoxy carbonyls; 85 top photolysis of silyl enol ethers with e- acceptors: 86 top other Mukaiyama aldol reactions: Scheme 2.2 CareyB-Chap2-5ed Chapter 2-5ed
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Asymmetric Aldol Additions (I)
Advanced Org Chem-Carey B Fall 2008 Asymmetric Aldol Additions (I) Stereoselections in aldol addition reactions simple diastereoselection: enolate stereochemistry cyclic TS: Z-enolates syn & E-enolates anti aldols diastereofacial selection chiral aldehydes & achiral enolates achiral aldehydes & chiral enolates chiral boronates for achiral aldehydes & enolates enantioselective catalytic Mukaiyama aldol additions double stereodifferentiation: matched & mismatched chiral aldehydes & chiral enolates CareyB-Chap2-5ed Chapter 2-5ed
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Asymmetric Aldol Additions (II)
Advanced Org Chem-Carey B Fall 2008 Asymmetric Aldol Additions (II) Diastereofacial selection: 89 bottom chiral aldehydes: Felkin-Anh model; 90 top & bottom double-gauche interaction: 3,4-anti with Z-enolates: 91 top chelation control: adjacent heteroatoms; a (syn), b (anti), 93 non-chelation with BF3 vs Ti: 94 bottom non-chelating heteroatoms: polar effects; 96 chiral enolates: Evans oxazolidinones; 115 top TiCl4: non-Evans syn aldol anti aldol products 116 middle CareyB-Chap2-5ed Chapter 2-5ed
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Asymmetric Aldol with Chiral Aldehydes
Advanced Org Chem-Carey B Fall 2008 Asymmetric Aldol with Chiral Aldehydes (A+B)/(C+D): simple diastereoselection (A+C)/(B+D): diastereofacial selection CareyB-Chap2-5ed Chapter 2-5ed
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Asymmetric Aldol Additions (III)
Advanced Org Chem-Carey B Fall 2008 Asymmetric Aldol Additions (III) Diastereofacial selection (continued) chiral boronates: absolute stereocontrol; 88 other chiral boronates: 86 bottom & 87 bottom enantioselective Mukaiyama reaction: 89 top chiral catalysts & reactions: Scheme Double stereodifferentiation: 109 top CareyB-Chap2-5ed Chapter 2-5ed
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Double Diastereoselection in Aldols (I)
Advanced Org Chem-Carey B Fall 2008 Double Diastereoselection in Aldols (I) Inherent selectivities: chiral aldehydes/enolates CareyB-Chap2-5ed Chapter 2-5ed
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Double Diastereoselection in Aldols (II)
Advanced Org Chem-Carey B Fall 2008 Double Diastereoselection in Aldols (II) Matched pair & mismatched pair CareyB-Chap2-5ed Chapter 2-5ed
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Intramolecular Aldol Reactions
Advanced Org Chem-Carey B Fall 2008 Intramolecular Aldol Reactions Facile cyclization for 5-/6-rings: 134 middle directed cyclization: ring-size & proximity; 135 Sch. 2.10 Robinson annulation: cyclohexenones; 136 middle Michael reaction & aldol condensation: 93 Scheme 2.10 Wieland-Miescher ketone: entry 1; for steroids & terpenes a Mannich base as an enone equivalent: entry 3 favored Michael reactions: a-silyl/thio; entries 6 & 7, 93 bot activation with Lewis acids: 91 bottom (cf. 41 bottom) enantioselective Robinson annulation: 95 middle via an enamine of L-proline (2 equiv): 95 bottom CareyB-Chap2-5ed Chapter 2-5ed
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Robinson Annulation: Hajos (Di)Ketone
Advanced Org Chem-Carey B Fall 2008 Robinson Annulation: Hajos (Di)Ketone CareyB-Chap2-5ed Chapter 2-5ed
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Enolate Addition to Imines & Iminiums (I)
Advanced Org Chem-Carey B Fall 2008 Enolate Addition to Imines & Iminiums (I) Reactivity: [C=OH]+ > [C=NR2]+ > C=O > C=NR imines: activated as iminiums under acidic conditions Mannich reaction: 96 middle & 97 Scheme 2.11 Mannich bases: 2o amines; RC(O)CH2-CH2NR2 Eschenmoser’s salt: Me2N+=CH2 I-; entries 4 & 5 (non-acidic) introduction of an a-methylene group to carbonyls: elimination of –NR2; entries 6-9 & 98 middle dialkylation with 1o amines: 96 bottom application to tropinone: an alkaloid derivative; 98 bottom CareyB-Chap2-5ed Chapter 2-5ed
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Advanced Org Chem-Carey B
Fall 2008 Mannich Reactions CareyB-Chap2-5ed Chapter 2-5ed
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Enolate Addition to Imines & Iminiums (II)
Advanced Org Chem-Carey B Fall 2008 Enolate Addition to Imines & Iminiums (II) N-acyl iminium ions: very reactive E+; 99 middle preparation: elimination of a-alkoxyamides reactions with neutral Nu & enolate: 99 bottom & 100 top Knoevenagel condensation: 102 Scheme 2.12 amine-catalyzed: via iminium ions to enones; 100 bottom use of active methylenes with 2 M: 101 top & mid concerted decarboxylative condensations: 101 bottom CareyB-Chap2-5ed Chapter 2-5ed
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Acylation of Enolates (I)
Advanced Org Chem-Carey B Fall 2008 Acylation of Enolates (I) Claisen condensation: b-ketoesters; 149 middle thermodynamic: >1 eq. weak base & esters with 2 a-Hs equilibration control: 150 middle & Scheme 2.14 kinetic control: complete formation of enolates; entry 2 Dieckmann condensation: intramolecular; entries 3-8 mixed condensation with different esters: non-enolizable & reactive esters as an acceptor; entries 9-12 Other acylating agents: RCOX, (RCO)2O, RCO(imid.) enolates preformed in inert solvents: 153 Scheme 2.15 reactivity: RCOX > (RCO)2O > RCO-imid. > RCO2R’ CareyB-Chap2-5ed Chapter 2-5ed
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Claisen Condensation between Esters
Advanced Org Chem-Carey B Fall 2008 Claisen Condensation between Esters CareyB-Chap2-5ed Chapter 2-5ed
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Acylation of Enolates (II)
Advanced Org Chem-Carey B Fall 2008 Acylation of Enolates (II) Other acylating agents (cont’d): 153 Scheme 2.15 O- vs C-acylation: Weinreb amide & RCO(imid.); 154 top Mg enolate: soluble in ether & C-acylation; entries 1-2 preparation: Mg in EtOH, 2 RMgX & HO2CCH2CO2R’ ( 152 bottom) or MgCl2 & R3N ( 154 middle) ready decarboxylation: b-ketoesters; 152 bottom & entry 10 formylation: HCO2R; b-keto aldehydes (hydroxymethylene), 155 middle & 156 Scheme 2.16 entries 1-2 carboxylation of ketones & esters: b-ketoacids/esters CO2 with MgCl2 & R3N / Mg(O2COMe)2: 154 mid & bot cyanoformates (Mander’s reagent): 155 bottom & entry 6 b-keto sulfoxides: similar to acylation; 155 bottom applications: similar to CO2R; 156 bottom & 157 top CareyB-Chap2-5ed Chapter 2-5ed
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Wittig Reactions (I): R3P+–-CR’2
Advanced Org Chem-Carey B Fall 2008 Wittig Reactions (I): R3P+–-CR’2 Condensation of ylides (ylenes) with carbonyls: 157 R2C=O + Ph3P=CR1R R2C= CR1R2 + Ph3P=O mechanism: addition followed by elimination; 158 bottom preparation of ylides: phosphonium salts; 159 top strong bases for weak carbon acids: unstabilized ylides, more reactive; entries 1-7, Scheme 2.17 KOtBu for hindered ketones: entries 10-11 weak bases for b-ketophosphonium salts: stabilized ylides, less reactive; entries 8-9 Stereoselectivity in the Wittig Reactions unstabilized ylidesZ-alkenes; stabilized ylidesE-alkenes CareyB-Chap2-5ed Chapter 2-5ed
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Mechanisms of Wittig Olefination
Advanced Org Chem-Carey B Fall 2008 Mechanisms of Wittig Olefination oxaphosphetane betaine H CareyB-Chap2-5ed Chapter 2-5ed
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Advanced Org Chem-Carey B
Fall 2008 Wittig Reactions (II) Stereoselectivity in the Wittig Reactions (continued) Z-alkenes: kinetic control; entries 3 & 5 vs 4 ‘salt-free’ conditions: Na (K) vs Li & aldehydes with branched R E-alkenes: thermodynamic control; entries 8-9 semi-stabilized ylides: intermediate selectivity; entry 6 the Schlosser modification: E-alkenes; 162 middle Z-allylic alcohol with HCHO (Corey): 162 bottom & entry 12 functionalized ylides: entries 13-16, 161 Scheme 2.17 methoxymethylene ylides: aldehydes/ketones; 163 top extended conjugated double bonds: 163 middle CareyB-Chap2-5ed Chapter 2-5ed
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Stereoselectivity of Wittig Olefination (I)
Advanced Org Chem-Carey B Fall 2008 Stereoselectivity of Wittig Olefination (I) concerted mechanism CareyB-Chap2-5ed Chapter 2-5ed
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frontier molecular orbital (FMO) theory by Fukui
orbital correlation method by Woodward & Hoffmann [4p+2p] p4* A LUMO antisymmetric (A) p* LUMO p3* S p2 A HOMO symmetric (S) p HOMO p1 S CareyB-Chap2-5ed
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Prohibited (Forbidden) Interactions
[2p+2p] LUMO LUMO p* A A S p S HOMO HOMO CareyB-Chap2-5ed
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[2ps+2pa] CareyB-Chap2-5ed
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Stereoselectivity of Wittig Olefination (II)
Advanced Org Chem-Carey B Fall 2008 Stereoselectivity of Wittig Olefination (II) reversible mechanism 45a 45b CareyB-Chap2-5ed Chapter 2-5ed
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Modifications of Wittig Reaction
Advanced Org Chem-Carey B Fall 2008 Modifications of Wittig Reaction CareyB-Chap2-5ed Chapter 2-5ed
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Related Wittig-Type Olefinations
Advanced Org Chem-Carey B Fall 2008 Related Wittig-Type Olefinations (Horner-)Wadsworth-Emmons reaction: 164 bottom phosphonate carbanions with a-M: Scheme 2.18 E-alkene, faster rate & soluble byproduct ((RO)3PO2-M+) preparation of phosphonates: Michaelis-Arbuzov reaction deprotonation with LiCl & R3N: & entries 9-10 Z-alkenes by modifications: additives / O=P(OR’)2; 165 top intramolecular reactions: rings; 166 middle & entries 7-8 Horner-Wittig reaction: 170 bottom phosphine oxide anion: stable b-hydroxy intermediate addition of phosphine oxide anion to carbonyls: Z-alkenes reduction of b-ketophosphine oxide: E-alkenes CareyB-Chap2-5ed Chapter 2-5ed
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(Horner-)Wadsworth-Emmons Reaction
Advanced Org Chem-Carey B Fall 2008 (Horner-)Wadsworth-Emmons Reaction CareyB-Chap2-5ed Chapter 2-5ed
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Horner-Wittig Reactions
Advanced Org Chem-Carey B Fall 2008 Horner-Wittig Reactions CareyB-Chap2-5ed Chapter 2-5ed
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Other Olefination Reactions
Advanced Org Chem-Carey B Fall 2008 Other Olefination Reactions Peterson reaction: b-hydroxylsilanes; 171 middle syn & anti elimination: basic & acidic conditions ; 172 top in-situ elimination: 171 middle & Scheme 2.19 selective elimination: faster syn; 172 bottom Julia olefination: b-hydroxylsulfones; 175 top Julia-Lythgoe olefination: reductive b-elimination; E-alkenes Julia-Kocienski olefination: in-situ syn-elimination; 175 mid 2-sulfonylbenzothiazole / 3,5-bis(trifluoromethyl)phenyl sulfones: 176 Scheme 2.20 CareyB-Chap2-5ed Chapter 2-5ed
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Sulfur Ylides: R2(O)S+–-CH2
Advanced Org Chem-Carey B Fall 2008 Sulfur Ylides: R2(O)S+–-CH2 Preparation of sulfonium/sulfoxonium ylides deprotonation of sulfonium/sulfoxonium salts: 177 middle Reactions with carbonyls: epoxides; 177 bottom sulfonium ylides: more reactive than sulfoxonium ylides sulfonium ylides: kinetic; sulfoxonium ylides: thermodynamic enones: 180 Scheme 2.21 & entries 5-6 ( 178 middle) stereoselectivity: axial vs equatorial; 179 top oxaspiropentanes: cyclobutanones; entry 13 & 179 middle stable sulfur ylides: sulfoximine anions; 179 bottom Reactions with E+: terminal alkenes; 181 top CareyB-Chap2-5ed Chapter 2-5ed
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Sulfur Ylides: Preparation & Reactions
Advanced Org Chem-Carey B Fall 2008 Sulfur Ylides: Preparation & Reactions CareyB-Chap2-5ed Chapter 2-5ed
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Darzens Condensation Reactions
Advanced Org Chem-Carey B Fall 2008 Darzens Condensation Reactions Addition of enolates of a-haloesters: 182 top production of a,b-epoxyesters: 182 Scheme 2.20 silylepoxides: anions of halomethylsilanes; 182 middle CareyB-Chap2-5ed Chapter 2-5ed
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Conjugate Addition of Enolates
Advanced Org Chem-Carey B Fall 2008 Conjugate Addition of Enolates Electrophilic C=C-/CC-EWG: 185 Scheme 2.23 Michael reactions: basic catalysis & reversible; 183 bot EWGs: carbonyls, nitro, cyano & sulfonyl thermodynamic enolates: catalytic amount of base, active hydrogen with 2 M groups, weak base (F-: 186 top) kinetic enolates: quantitative formation of enolates & 1,5-dicarbonyl products; 187 Scheme 2.24 1,2- vs 1,4-addition: -78 oC vs 25 oC; entry 3 good Michael acceptors: a-stabilizing group; Si, S, S=O, CN CareyB-Chap2-5ed Chapter 2-5ed
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Conjugate Addition of Enolates (II)
Advanced Org Chem-Carey B Fall 2008 Conjugate Addition of Enolates (II) CareyB-Chap2-5ed Chapter 2-5ed
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Stereoselectivity in Conjugate Additions
Advanced Org Chem-Carey B Fall 2008 Stereoselectivity in Conjugate Additions Diastereoselective conjugate addition: 188 middle anti – Z-enolates & syn – E-enolates: chelation control enhanced selectivity with Ti(i-PrO)4: 191 bottom cyclic enamines: axial attack (stereoelectronic); 193 mid addition of organometallics: 1,2- vs 1,4-; 197 mid-198 top Absolute facial selectivity of enones substrate control: 193 bottom, 197 top & 196 bottom reagent control: chiral bis-oxazoline cat.; 196 middle CareyB-Chap2-5ed Chapter 2-5ed
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Conjugate Addition of Enolate Equivalents
Advanced Org Chem-Carey B Fall 2008 Conjugate Addition of Enolate Equivalents Tandem reactions: 189 bottom- 190 top successive addition-alkylation: trans stereoselectivity Lewis acid-catalyzed conjugate additions: 190-1 Mukaiyama-Michael reactions: [Ti], [Mg], [Li]; anti (open TS) nitro groups as an oxo equivalent: 1,4-diketones; 192 bot F- as an activator: anionic enolates; 193 top Conjugate addition of –CN [-COY or -CH2NH2] reactive -CN: Et3Al-HCN, Et2Al-CN; 199 top stereoselective addition: 199 bottom CareyB-Chap2-5ed Chapter 2-5ed
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