1. Chapter 2. Addition to Carbonyl Groups
Advanced Org Chem-Carey B
Fall 2008
Chapter 2. Addition to Carbonyl Groups
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2. Enolates Addition to Carbonyl Groups
Advanced Org Chem-Carey B
Fall 2008
Enolates Addition to Carbonyl Groups
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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
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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
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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
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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
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7. Formation of Z-enolates: Equilibration
Advanced Org Chem-Carey B
Fall 2008
Formation of Z-enolates: Equilibration
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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
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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
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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
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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
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12. Asymmetric Aldol with Chiral Aldehydes
Advanced Org Chem-Carey B
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Asymmetric Aldol with Chiral Aldehydes
(A+B)/(C+D): simple diastereoselection
(A+C)/(B+D): diastereofacial selection
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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
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14. Double Diastereoselection in Aldols (I)
Advanced Org Chem-Carey B
Fall 2008
Double Diastereoselection in Aldols (I)
Inherent selectivities: chiral aldehydes/enolates
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15. Double Diastereoselection in Aldols (II)
Advanced Org Chem-Carey B
Fall 2008
Double Diastereoselection in Aldols (II)
Matched pair & mismatched pair
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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
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17. Robinson Annulation: Hajos (Di)Ketone
Advanced Org Chem-Carey B
Fall 2008
Robinson Annulation: Hajos (Di)Ketone
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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
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19. Advanced Org Chem-Carey B
Fall 2008
Mannich Reactions
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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
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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’
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22. Claisen Condensation between Esters
Advanced Org Chem-Carey B
Fall 2008
Claisen Condensation between Esters
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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
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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
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25. Mechanisms of Wittig Olefination
Advanced Org Chem-Carey B
Fall 2008
Mechanisms of Wittig Olefination
oxaphosphetane
betaine H
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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
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27. Stereoselectivity of Wittig Olefination (I)
Advanced Org Chem-Carey B
Fall 2008
Stereoselectivity of Wittig Olefination (I)
concerted mechanism
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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
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30. [2ps+2pa]
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31. Stereoselectivity of Wittig Olefination (II)
Advanced Org Chem-Carey B
Fall 2008
Stereoselectivity of Wittig Olefination (II)
reversible mechanism
45a
45b
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32. Modifications of Wittig Reaction
Advanced Org Chem-Carey B
Fall 2008
Modifications of Wittig Reaction
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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
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34. (Horner-)Wadsworth-Emmons Reaction
Advanced Org Chem-Carey B
Fall 2008
(Horner-)Wadsworth-Emmons Reaction
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35. Horner-Wittig Reactions
Advanced Org Chem-Carey B
Fall 2008
Horner-Wittig Reactions
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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
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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
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38. Sulfur Ylides: Preparation & Reactions
Advanced Org Chem-Carey B
Fall 2008
Sulfur Ylides: Preparation & Reactions
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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
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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
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41. Conjugate Addition of Enolates (II)
Advanced Org Chem-Carey B
Fall 2008
Conjugate Addition of Enolates (II)
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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
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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
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