Carbon-Carbon Bond Forming Reactions
Anionic : R + X R X
Cationic : R + X R X
Radical : R + X R X
Electrocyclic :
a) Diels-Alder
b) Copec) Claisen X
X
Carbon-Carbon Bond Forming Reactions
I. Substitution Reaction
R + X R
R'
R'
II. Addition Reaction
R + X R X
R' R'
Carbon-Carbon Bond Forming Reactions
I. Substitution Reaction
R + X R
R'
R'
a. More Acidic Carbon Centers : cyanide, acetylide, hetero-atom substituted centers
b. Less Acidic Carbon Centers : alkyl anions
Acidity of compounds --http://daecr1.harvard.edu/pKa/pka.html
Chapter 1 : Alkylation of enolates, enamines, imine anions
Mostly SN2 type
Y
X
H:Base
Y
X
W W
R X
Y
X
R
W
RXN. Depends on the solvent counter ion temperature structure additives
1. Generation of carbanion by Deprotonation
Y
X
H :Base Y
X
W W
+ + H:Base
Y
X
W
Stabilization by resonance induction
Activating Power : NO2 > RCO > RSO2 > COOH, COOR, CN, CONH2
** extra-alkyl group increases pKa
Base : NaNH2, n-BuLi, NaOR, NaH, LiNR2
** Stronger base is required for complete conversion **
1. Generation of carbanion by Deprotonation
** Comparison of pKa values is important **
Some bases are nuclephiles as well !!!
Y
O
H + NaNH2Y
O-
+ NH3
Y
O
H + LDAY
O-
+ HN
Y
O
H + NaOEt
Y
O-
+ EtOH
RO
O+ NaOR
OR
O
RO
O+ HOR
OR
O
Na
2-1. Regioselectivity in enolate formation
Under kinetic control : strong base, aprotic solvent, complete consumption of the ketone
O-
+ BaseO O-ka kb
If ka > kb
Major product is O-
Under thermodynamic control : at Equilibrium – excess ketone, protic solvent or slow deprotonation
An enolate through Kinetic Control is easier to obtain exclusively than the other enolate through Thermodynamic Control.
O-
+ BaseO
2-2. Stereoselectivity in enolate formation
Major thermodynamic control
O-
kinetic control Major
N
H
O
Li
Small
Large
T.S. for kinetic product
Not Real
2-3. Enantioselectivity in enolate formation
Chiral bases enable to distinguish enantiotopic protons.
O
Ha Hb
NLiN
TMSCl
OTMS
Hb
95%, 84% e.e.
3. Other means to generate enolate (exclusive generation of single isomeric enolate)
a. From TMS ethers
O TMSCl, Et3N OTMS OTMS+
OTMS+ MeLi
O-
+ BnMe3NFO-
Ph
OAc+ 2MeLi Ph
O-
3. Other means to generate enolate (exclusive generation of single isomeric enolate)
O
Li/NH3
b. From enones
-O
NH3
-O
O
O
O TMSCl
"Pt" or "Cu"
OTMS
O
O
4. Alkylation of enolates
a. Generation of enolates
Amide base : LDA (since 1968) : for less acidic proton
N
LiN
Li
SiN
Li
Si
Stable under 0oC Non-nucleophilic Stable at r.t.No reducing ability
NaOEt/EtOH, or NaH/solvent : for more acidic proton
DBU, DBNEt3N NaOH
strong non-ionic base : Phosphazene base Synlett 752(2000) and ref.
N
P
N N
NEt2
t-Bu
NMe2
PMe2N NMe2
N
PMe2N
NMe2
NEt
BEMP P2Et
NMe2
PMe2N NMe2
N
PN
N
Nt-Bu
P
NMe2
NMe2
Me2N
PMe2N NMe2
NMe2
P4t-Bu
pKa=27.6 pKa=32.7 pKa=42.1
strong non-ionic base : Phosphazene base Synlett 752(2000) and ref.
BuLi 67 : 33
O
PhO
Phbase
Br O
PhO
Ph O
PhO
Ph
P4tBu 98 : 2
JOC 5343(1994)
4. Alkylation of enolates
b. Factors affecting alkylation process : ** SN2 reaction**
i) Electrophile : mostly primary alkyls. Secondary reacts very slow Tertiary does not substitue.
Methyl, allylic, benzylics are most reactive
ii) Solvent : the more polar, the faster the reaction it’s more related to the aggregation state of enolates
iii) Counter ion : “ more naked anion is more reactive”
OM
M : Li, Mg, Na, K, NR4More reactive
iv) Additives : TMEDA, HMPA, Crown ether ( 18-C-6 : Na+, K+
12-C-4 : Li+ )
4. Alkylation of enolates
b. Malonate ester, ketoester synthesis
i) Monoalkylation v.s. Dialkyation
Formation of cyclic compounds ; rates (3>5>6>4)
ii) Decarboxylation ; Krapcho (TL, 215(1967)) nucleophilic, nonhydrolytic
c. Alkylation of dianions
OEt
O O NaHOEt
O O
Na
LDA
OEt
O- O- R-X
OEt
O OR
4. Alkylation of enolates
d. O-alkylation v.s. C-alkylation
i) More naked anion gives more O-alkylation : K+ with HMPAii) Hard electrophile prefers O-alkylation : X= OTs, OTf
O-
R-XO OR
O R R-X
-O
Br
O
-O
Br
O
conformational effect
OEt
OLDA
OEt
O-
H+
OEt
O
E+
OEt
O
E
Alkylation of conjugated enolate
4. Alkylation of enolates
e. Alkylation of aldehyde : self-condensation is fast.
Used base : KH, KNH2
H
O O-
O n-BuLi
room temp.
O LiO
TL 3791 (1977)
f. Acid derivatives : acid, ester, amide, nitrile, lactone, lactam – more reactive
Nitrile anion reacts well with epoxides
O
CN NC
LDAOH
COOH
2LDAOLi
OLi
R X
R COOH
Acid derivatives offer chiral auxiliaries for asymmetric alkylation
Evans’ chiral oxazolidinone
O N
O O
RR'
O N
O O
RR'
LDA
Li
O N
O O
RR'
E-X
E
E : alkyl, halogen nitrogen, sulfur
4. Alkylation of enamines, imine anions
a. enamines
Neutral, isolable enolate equivalent – more nucleophilic than enolate
Robinson Annulation
ONH
H+
N i) R-X
ii) H3O+
OR
ONH
H+
N
ii) H3O+
OO
4. Alkylation of enamines, imine anions
b. Imine anion : metalloenamine
reactive enolate equivalent
Chiral induction possible
NR
EtMgBr
or LDA
NR M R'-X O
R'
LDANOMe N
LiO
NLiOPh
XR
R-X NOMe
R
c. Hydrazone anion
NN
n-BuLi NN M
NN
i) n-BuLi
ii) MeI
NN
4. Conjugate addition of enolates : Michael addition
Lewis acid with silyl enolether
Can be carried out with catalytic amount of base : depends on enolate.
Successive reaction is possible.
Diethylaluminum Cyanide : CN-
O+
OEt
O-
O-
EtOOC
BrO
EtOOC
Enamine for Robinson Annulation
Homewrok
Problems : 2, 4, 7, 9, 11, 13, 15, 19, 20
Due date :
Top Related