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Chapter 2. Addition to Carbonyl Groups

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1 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

2 Enolates Addition to Carbonyl Groups
Advanced Org Chem-Carey B Fall 2008 Enolates Addition to Carbonyl Groups CareyB-Chap2-5ed Chapter 2-5ed

3 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

4 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

5 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

6 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

7 Formation of Z-enolates: Equilibration
Advanced Org Chem-Carey B Fall 2008 Formation of Z-enolates: Equilibration CareyB-Chap2-5ed Chapter 2-5ed

8 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

9 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

10 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

11 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

12 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

13 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

14 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

15 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

16 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

17 Robinson Annulation: Hajos (Di)Ketone
Advanced Org Chem-Carey B Fall 2008 Robinson Annulation: Hajos (Di)Ketone CareyB-Chap2-5ed Chapter 2-5ed

18 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

19 Advanced Org Chem-Carey B
Fall 2008 Mannich Reactions CareyB-Chap2-5ed Chapter 2-5ed

20 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

21 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

22 Claisen Condensation between Esters
Advanced Org Chem-Carey B Fall 2008 Claisen Condensation between Esters CareyB-Chap2-5ed Chapter 2-5ed

23 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

24 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 ylidesZ-alkenes; stabilized ylidesE-alkenes CareyB-Chap2-5ed Chapter 2-5ed

25 Mechanisms of Wittig Olefination
Advanced Org Chem-Carey B Fall 2008 Mechanisms of Wittig Olefination oxaphosphetane betaine H CareyB-Chap2-5ed Chapter 2-5ed

26 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

27 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

28 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

29 Prohibited (Forbidden) Interactions
[2p+2p] LUMO LUMO p* A A S p S HOMO HOMO CareyB-Chap2-5ed

30 [2ps+2pa] CareyB-Chap2-5ed

31 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

32 Modifications of Wittig Reaction
Advanced Org Chem-Carey B Fall 2008 Modifications of Wittig Reaction CareyB-Chap2-5ed Chapter 2-5ed

33 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

34 (Horner-)Wadsworth-Emmons Reaction
Advanced Org Chem-Carey B Fall 2008 (Horner-)Wadsworth-Emmons Reaction CareyB-Chap2-5ed Chapter 2-5ed

35 Horner-Wittig Reactions
Advanced Org Chem-Carey B Fall 2008 Horner-Wittig Reactions CareyB-Chap2-5ed Chapter 2-5ed

36 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

37 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

38 Sulfur Ylides: Preparation & Reactions
Advanced Org Chem-Carey B Fall 2008 Sulfur Ylides: Preparation & Reactions CareyB-Chap2-5ed Chapter 2-5ed

39 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

40 Conjugate Addition of Enolates
Advanced Org Chem-Carey B Fall 2008 Conjugate Addition of Enolates Electrophilic C=C-/CC-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

41 Conjugate Addition of Enolates (II)
Advanced Org Chem-Carey B Fall 2008 Conjugate Addition of Enolates (II) CareyB-Chap2-5ed Chapter 2-5ed

42 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

43 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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