Chapter 2. Structure and Properties

Chapter 2. Structure and Properties

Chapter 2. Addition to Carbonyl Groups O- R' Y O R O Y Nu:- C+ R Y Y R 1. Nu: Nu Nu H+ Nu - Y = good leaving group OH CareyB-Chap2-5ed

O + 2. H - -Y Y Nu -O X O R Nu OH R X R' H =C Nu + R - X -

CHR' Nu R Y O R' H Nu NR Nu=NHR R - H2O Y Y= Un - H sat . 2O R'HC Y Unsat. Nu 1

Enolates Addition to Carbonyl Groups O O R1 carbonyls R2 O base + H R3 aldehyde R1 R1 = alkyl/aryl RO O- RO R2 CareyB-Chap2-5ed R2 - OR R3 R2 aldol product R1 = OR (self-condensation) O

OH O O RO R2 -keto esters - H2O O R2 R1 R3 R2 condensation product 2 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 greater atoms: Zimmerman-Traxler model; 68 top selectivity with Z-enolates: 69 top & 70 Table 2.1 alternative CareyB-Chap2-5ed transition-state models for aldol reactions cyclic ketones: only E-enolates; 69 middle more stable anti: by equilibration; 71 middle 3 Diastereoselective Aldol Reactions O + R3 H R2 OM

H 1 R + R3 H H 2 O R3 R1 R2 syn (erythro) Z-enolate O OH OH OM 1 R R E-enolate R3

O R1 anti (threo) R2 Generalizations CareyB-Chap2-5ed 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 4 Alternative Models (III): Open TS Noyori JACS 1977, 99, 1265 & 1981, 103, 2106 R1 syn (major) OM R3 H R2 H O R1

anti (minor) H R2 H O syn CareyB-Chap2-5ed R3 R2 R1 H H anti (minor) Z-enolate O OM R3 MO MO R3 H R1 H R2

syn (major) E-enolate O aldols irrespective of the enolate geometry 5 Boron Enolates Higher selectivity: cyclic chair TS; 72 top more compact TS larger steric interaction: B-O 1.36-1.47 ; Li-O 1.92-2.00 ; Mg-O 2.01-2.03 ; 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: CareyB-Chap2-5ed equilibrated boronation of silyl ethers; 73 middle highly stereoselective enolate preparation: ketones, esters

no further chelation to intramolecular electron donor atoms 6 Formation of Z-enolates: Equilibration TMSO (CH3)3C CareyB-Chap2-5ed H CH3 9-BBN-Br BBNO (CH3)3C CH3 H 9-BBN-Br TMSO (CH3)3C CH3 H 7 Other Metal Enolates: Ti, Sn, Zr

Ti enolates: chair TS & stronger chelation; 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 CareyB-Chap2-5ed 74 bot cyclic TS but less selective: B > Zr > Li; 78 top 8 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+: cat. Yb(OTf)3 in aqueous solvent: affinity to C=O; 84 middle InCl 3 : faster ligand exchange & proper acidity; 84 bottom acetals CareyB-Chap2-5ed active catalyst; 83 middle & 84 top as electrophiles: -alkoxy carbonyls; 85 top photolysis of silyl enol ethers with e- acceptors: 86 top other Mukaiyama aldol reactions: 87-88 Scheme 2.2 9 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 chiral aldehydes & chiral enolates boronates for achiral aldehydes & enolates enantioselective double stereodifferentiation: matched & mismatched chiral CareyB-Chap2-5ed catalytic Mukaiyama aldol additions aldehydes & chiral enolates 10 Asymmetric Aldol Additions (II) Diastereofacial selection: 89 bottom

chiral aldehydes: Felkin-Anh model; 90 top & bottom double-gauche chelation interaction: 3,4-anti with Z-enolates: 91 top control: adjacent heteroatoms; a (syn), (anti), 93 non-chelation with BF3 vs Ti: 94 bottom non-chelating CareyB-Chap2-5ed heteroatoms: polar effects; 96 chiral enolates: Evans oxazolidinones; 115 top TiCl 4 : non-Evans syn aldol anti aldol products 116 middle 11 Asymmetric Aldol with Chiral Aldehydes (A+B)/(C+D): simple diastereoselection (A+C)/(B+D): diastereofacial selection CareyB-Chap2-5ed 12

Asymmetric Aldol Additions (III) Diastereofacial selection (continued) chiral boronates: absolute stereocontrol; 88 other enantioselective Mukaiyama reaction: 89 top chiral CareyB-Chap2-5ed chiral boronates: 86 bottom & 87 bottom catalysts & reactions: Scheme 2.7-2.8 Double stereodifferentiation: 109 top 13 Double Diastereoselection in Aldols (I) Inherent selectivities: chiral aldehydes/enolates O O O + H O

O O Ph OH OH *R Ph 79 : 21 O + OTMS O + Ph *R1 1 O O CareyB-Chap2-5ed O LDA O LDA

H O O R OH O 2 + R * R OH R2* 18 : 78 14 Double Diastereoselection in Aldols (II) Matched pair & mismatched pair O O + H 1 O LDA *R

O O OH O + R * *R1 1 2 *R OH R2* 62 : 28 O O 1 *R CareyB-Chap2-5ed O LDA + H O O

1 *R OH O + R * *R1 2 OH R2* 100 : 0 15 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 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 CareyB-Chap2-5ed ketone: entry 1; for steroids & terpenes an enamine of L-proline (2 equiv): 95 bottom 16 Robinson Annulation: Hajos (Di)Ketone O O O O KOH + O - H2O KOH O O

O CareyB-Chap2-5ed O O OH 17 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 Eschenmosers 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 CareyB-Chap2-5ed to tropinone: an alkaloid derivative; 98 bottom 18 Mannich Reactions CareyB-Chap2-5ed 19 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

CareyB-Chap2-5ed decarboxylative condensations: 101 bottom 20 Acylation of Enolates (I) Claisen condensation: -ketoesters; 149 middle thermodynamic: >1 eq. weak base & esters with 2 a-Hs equilibration CareyB-Chap2-5ed control: 150 middle & 151-2 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 21 Claisen Condensation between Esters CareyB-Chap2-5ed 22 Acylation of Enolates (II) Other acylating agents (contd): 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: -ketoesters; 152 bottom & entry 10 formylation: HCO2R; -keto aldehydes (hydroxymethylene), 155 middle & 156 Scheme 2.16 entries 1-2 carboxylation of ketones & esters: -ketoacids/esters

CO 2 with MgCl2 & R3N / Mg(O2COMe)2: 154 mid & bot cyanoformates CareyB-Chap2-5ed (Manders reagent): 155 bottom & entry 6 -keto sulfoxides: similar to acylation; 155 bottom applications: similar to CO2R; 156 bottom & 157 top 23 Wittig Reactions (I): R3P+-CR2 Condensation of ylides (ylenes) with carbonyls: 157 R2C=O + Ph3P=CR1R2 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, 160-161 Scheme 2.17 KOtBu for hindered ketones: entries 10-11 weak bases for -ketophosphonium salts: stabilized ylides, less reactive; entries 8-9 Stereoselectivity in the Wittig Reactions CareyB-Chap2-5ed unstabilized ylidesZ-alkenes; stabilized ylidesE-alkenes 24 Mechanisms of Wittig Olefination betaine oxaphosphetane H CareyB-Chap2-5ed 25 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 extended CareyB-Chap2-5ed ylides: aldehydes/ketones; 163 top conjugated double bonds: 163 middle 26 Stereoselectivity of Wittig Olefination (I) concerted mechanism

Ph Ph P Ph H O C 1 R C H R2 tilted approach CareyB-Chap2-5ed Ph Ph P O Ph C H 1 R C 2 R H parallel approach 27

frontier molecular orbital (FMO) theory by Fukui orbital correlation method by Woodward & Hoffmann C C antisymmetric (A) * [4+2] LUMO LUMO symmetric (S) CareyB-Chap2-5ed HOMO C C C C 4* A 3* S

2 A 1 S HOMO 28 Prohibited (Forbidden) Interactions [2+2] C C CareyB-Chap2-5ed C C A * LUMO LUMO S HOMO HOMO A

S 29 [2s+2a] CareyB-Chap2-5ed 30 Stereoselectivity of Wittig Olefination (II) reversible mechanism O O + 1 R PPh3 H H 2 + H C + 1

R 45a CareyB-Chap2-5ed R - O PPh3 PPh3 H R 2 H 1 R R 2 H 45b 31 Modifications of Wittig Reaction

O O + 1) CH2 O R RLi RCHCH PPh3 RCHC PPh3 R' 25C R' 2) 25C H betaine -oxido ylide CareyB-Chap2-5ed CH2OH R' 32 Related Wittig-Type Olefinations (Horner-)Wadsworth-Emmons reaction: phosphonate carbanions with a-M: 167-8 Scheme 2.18 E-alkene, faster rate & soluble byproduct ((RO)3PO2-M+) preparation of phosphonates: Michaelis-Arbuzov reaction deprotonation

with LiCl & R3N: 165-6 & 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 -hydroxy intermediate addition of phosphine oxide anion to carbonyls: Z-alkenes reduction CareyB-Chap2-5ed 164 bottom of -ketophosphine oxide: E-alkenes 33 (Horner-)Wadsworth-Emmons Reaction (RO)3P + R'-X CareyB-Chap2-5ed O R heat (OR)2P R' X- O + R'-X (OR)2P R'

34 Horner-Wittig Reactions CareyB-Chap2-5ed 35 Other Olefination Reactions Peterson reaction: -hydroxylsilanes; 171 middle syn & anti elimination: basic & acidic conditions ; 172 top in-situ elimination: 171 middle & 173-4 Scheme 2.19 selective elimination: faster syn; 172 bottom Julia olefination: -hydroxylsulfones; 175 top Julia-Lythgoe olefination: reductive -elimination; E-alkenes Julia-Kocienski olefination: in-situ syn-elimination; 175 mid 2-sulfonylbenzothiazole CareyB-Chap2-5ed

/ 3,5-bis(trifluoromethyl)phenyl sulfones: 176 Scheme 2.20 36 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 CareyB-Chap2-5ed 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 37 Sulfur Ylides: Preparation & Reactions CareyB-Chap2-5ed 38 Darzens Condensation Reactions CareyB-Chap2-5ed Addition of enolates of a-haloesters: 182 top production of a-epoxyesters: 182 Scheme 2.20 silylepoxides: anions of halomethylsilanes; 182 middle 39 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 & 1,5dicarbonyl products; 187 Scheme 2.24 1,2- vs 1,4-addition: -78 oC vs 25 oC; entry 3 good CareyB-Chap2-5ed Michael acceptors: a-stabilizing group; Si, S, S=O, CN 40 Conjugate Addition of Enolates (II) - O H X O + R' Z R

R more basic H Y C CH2 R1 Y CHR1 + CH2 C Z R2 O - RC-CCHCH=CR" R' CareyB-Chap2-5ed O RC CR2 + H C Z R2 R' O Z R H Y C CH2 + R2CH Z R1

O- R O R'CH CHC C CR R" R O R'CH CHCR" 1,2-addition 1,4-addition ArCHC N + Li Z S-H - less basic O R' R' O PhCH CHCCH3 [1,2-anion] [1,4-anion] H+ NC O CH3 Ar

Ph 41 Stereoselectivity in Conjugate Additions CareyB-Chap2-5ed 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

42 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 F- CareyB-Chap2-5ed groups as an oxo equivalent: 1,4-diketones; 192 bot 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 43

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