chapter 26–29 advanced enol and enolate...
TRANSCRIPT
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