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 :