Chapter 26–29 advanced enol and enolate chemistry
Common carbon acid pKa’s, common bases Enolate alkylation, aldol, Mukaiyama aldol, enamines The Wittig reaction Wittig variants: stabilized enolate-ylides and the Wittig-Horner reaction Imines as electrophiles: Mannich reaction and Robinson tropinone synthesis Conjugate additions: Michael reactions Other nucleophiles for conjugate additions
pKa’s to help you navigate organic mechanisms
H
H
CNH
O
EtOH
OH
~50
41
25
21
19
H
OH
O
EtO OEt
O
H
O2NH
O O
H
17
13
10
9
Li
NLi
O– K+
O– K+ 20
~50
36
NEtEt Et 9–10
14–16
Carbon acids Commonly used bases
(pKa’s of conjugate acids)
Alkylations of nitriles, nitro compounds, lactones, esters…
Ph CN
Ph CN
1) NaOH2) RX
R
CN
MeOC
NMeO
1) 2 eq. NaH2) 2 eq. MeI
Me NO2 NO2
O
EtO
1) Et3N2)
BrO
EtO
Br NO2
NO2NaHCO3
O
O 1) LDA, –78 °C2) MeI
O
O
OMe
O
OMe
O1) LDA, –78 °C2) BnBr
Kinetic and thermodynamic enolate alkylation
O 1) NaOEt, RT2) BnBr
O
O 1) LDA, –78 °C2) BnBr
O
O 1) LDA, –78 °C2) MeI O O
not
A laundry list of aldol reactions
O O O OHHO–/H2O or H3O+
O+ aldol
O
H
O
Ph
1) LDA
2)
O
Ph
OH Cross aldol (non-enolizable aldehyde)
OSiMe3
H
O
Ph+
O OH
PhTiCl4
Cross aldol (using a silyl enol ether)
O2N
O
H Et3NO2N
HO Henry reaction+
Aldol-type chemistry with esters
EtO
O
EtO
O NaOEtEtO
O O Claisen condensation+
EtO
OOEt
O
O O
OEtNaOEt Dieckmann condensation
OOEt
O
NaOEtO
O
Dieckmann condensation
OEt
O O NaOH+ Cross Claisen (x2)
OEt
O
O
O
O
The Wittig reaction
Ph3P RBuLi
Ph3P R
ylide"two opposing charges
on neighbouring atoms"
H R'
O
Br RPPh3
Br– R R' RR'+
Ph3P
RH R'
O
H
Ph3P
R H HR'
O–Ph3P
R H HR'
O Ph3P O
R R'
+
betaine
Moderate to high Z-selectivity
oxaphosphetane
Enolate/Wittig hybrids: E-selectivity from Wittig-type chemistry
BrOEt
OPh3P
PPh3
Br–
OEt
O
NaHPh3P
OEt
O–
H R'
O
R'R'+
OEtO
O
EtO
highly E-selective
BrOEt
OP
P(OEt)3 OEt
O
NaH H R'
O
R'R'+
OEtO
O
EtO
even more E-selective
EtO
O
EtOP
OEt
O–
EtO
O
EtO
POEt
O
EtO
O–
EtO
Stabilized Wittig reagents
Stabilized Wittig-Horner reagents
Wittig and Wittig-Horner examples
PPh3H R
OR
Z : ER
Cyclohexylt-BuPh
86:1498:287:13
PPh3EtO2CH
O
EtO2C 5:95
PEtO
O
OEt
O
OEt
OEtO2C
0:100
P OEt
O
OEt OMe
O
H
OMe
0:100
Imines as electrophiles: Mannich reaction
H
O
HH2N R
MeO OMe
O O
MeO OMe
O O
HNR
H+ But how do we ensure selectivity in this three-component reaction?
Mannich reaction examples
Robinson tropinone synthesis: 1917!! N
Me
O
O
Atropine
OH
H
O
HH2N R
MeO OMe
O O
MeO OMe
O O
HNR
H+
O
NH H
O
H
O
NMe2NaOH
1) NaOH, H2O2) HCl, ∆ (–CO2)
HO
O
HN
R
HO2C CO2HO
MeNH2 OHC CHON
Me
OHO2C
CO2H
Double Mannich HCl, ∆
(– 2 CO2)
NMe
O
Tropinone
Michael reaction: conjugate addition of enolates
EtO2C
MeO2C CO2Me
OEt
OMeO2C CO2Me
EtO2C OEtO–
MeO2C CO2Me
EtO2C CO2Et
Michael reactions of enolates are thermodynamically driven — Stabilizing either the enolate donor or the Michael acceptor (or both, as above) with an additional electron-withdrawing group favors conjugate addition over direct addition.
ratio ?
OTMS
EtO2CNO2
O CO2EtNO2
O NO2CO2Et+
O
O
O
H
O O
O
O
H
O
+
+HOO
BrOEt
O
1) NaH,
2) NaOEt, EtOH
TiCl4
OMe2CuLiMeMgCl
HO Me O
Me
NBoc
S PhO O
BrH2N N
Boc
O2S Ph
HN Ar NBoc
O2S
Ph
HN Ar+
O
PhSH
OPhS
NO2 OMe
O+
K2CO3 OMe
ONO2
Other nucleophiles for conjugate additions
Organocuprates
Amines
Thiols
Nitroalkane anions
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