Chapter 4. Equilibrium of the compositions of Grignard reagents.

Chapter 4

Equilibrium of the compositions of Grignard reagents

n-butyllithium and potassium t-butoxide(super base)

CH2C(CH3)3 CH2

Cn-BuLi

KOC(CH3)3

CH3

CH2Li

C C

CH2

CH3 CH2

CH3

C C

CH2

LiH2C CH2

CH2Lin-BuLi

KOC(CH3)3

Metal-halogen exchange

forming the morestable organolithium reagentRX R'Li RLi R'X+ +

C C

H

Ph Ph

H t-BuLi'

THF-Et2O

C C

H

Ph Li

H

pentane-

greater stability of sp2 carbanions

Retention of configuration

Metal-halogen exchange

Metal-halogen exchange

Reduction of sulfides

O

SPh

O

Li

LDMAN

PhSCSi(CH3)3

CH3

CH3

LDMANLiCSi(CH3)3

CH3

CH3

dimethylaminonaphthalene(LDMAN)

PhCH2CH2SPh PhCH2CH2LiLi or

Shapiro reaction

NHNTs

C2H5

CH3

Li

C2H5

CH3

2 n-BuLi

TMEDA

vinyllithium compounds

OTBS

NNHSO2ArOPN

OBnTPSO

OHCOBn

OPN

OBn

OBn

OTBS

OHH

TPSO

+

n-BuLiTHF,then

-78 C0 C¡£

¡£

I-Pr

I-Pr

I-Pr

Ar =15, 67 98:R = Piv

Nicolaou et al. J.Am.Chem.Soc.Vol.117,No.2,1995,634.

Reactions with Alkylating Agents Limited in scope Radicals involved

n-C4H9Br n-C4H9Li

CH(CH3)2

CH3(CH2)6CH3 CH3CH2CH=CH2CH3CH2CH2CH3+ + +

(43%) (3%) (19%)

disproportionation

+

C

CH3

CH3

C

CH3

CH3 (18%)

coupling of radicals

Hydrogen abstraction

CHCH2

CH2

ClLi

PhPhCH2CH=CH2

C14

**

~75%

Alkylation by allylic halides

Allyllithium and benzyllithium reagents

PhCH2LiC

CH2CH3

BrH

CH3

C

CH2CH3

H

CH3PhCH2(58% yield,100% inversion)

S 2N

C=CCH3

H

CH3

Br

C=CCH3

H

CH3

CH3(CH2)3

LiCH3(CH2)3I

1)2)

RI or RBr(77%)

Ring closureCH2I

CH2I

t-BuLi

(97%)

Grignard reagentsCH3

CH3 CH3

CH3 BrCH3

CH3 CH3

CH3 CH2CH=CH2Mg

CH2=CHCH2Br

MeX, X, ArCH2X

1)2)

(79%)

Reaction with Carbonyl Compoundds addition of Grignard reagents

MgR

X

OR'

R'Mg - R

XC O Mg R

R'

R'

R

CR'

R

O Mg

X

R

MgX2

termolecular complex

+

+H O2

nitriles

RMgX R'C N RCR' RCR'

NMgX O

+H O2

O

C N

CH3MgIHCl (52-59%)

CCH3

O

CH3(CH2)5MgBr CH3CH2CH2CCl CH3(CH2)5C(CH2)2CH3

O-30 CTHF

excess at low temperature

¡£

(92%)

+

good leaving group

NH

S

+

Competing reactionsMeerwein- Pondorff-Verley reduction

With hindered ketones

H

OMg

R

R

R

R

R'

R'

X

R

R

R

R

O

R'R'

H

Mg

X

+

cyclic T.S

Enolization of the ketone

ROMgX R'CCR''2 ROH

RMgX

RH

R'C=CR''2H

+

R'CCR''2

O

H

-

++

O O

HFacilitate by alkoxide

1 2 3 4 123 4123

4

homoallylic system

Lewis acid

directed ortho lithiation

CN(C2H5)2

CH3O

CH3O

CN(C2H5)2

CH3O

CH3O

Li

CH3

CH3O

O=CH

OMe

C=O

OH OMeOMe

CH3O

OMeCH3

(C2H5)2N

t-BuLi

(63%)

+(CH3)3COCHCH=CH2CH3(CH2)5I

C=CH

(CH3)3CO

H

(CH2)6CH3

(86%)allylic shiftLi

stable at low temperature

(DMF)

CH3(CH2)3CHCH=O BrCHCO2C2H5 CH3(CH2)3CHCHCHCO2C2H5

C2H5 CH3 CH3C2H5

OH

H+

1)2)

H O2+

(87%)

(97%)

Lewis acid Catalysis:O

Br

PhCH=OEt2AlCl

O

CHPh

OH-20 C

¡£

Zn+

+ +

mechanism

[R2Cu] R'CH=CHCR R2Cu R'CH=CHCR

O

RCu

O

R'CH=CHCR

O--£®

R

- +

fast electron transfer step no free radicals are generated

Heck reactions:

C=CC6H13

H

I

H

C=C

H

BrMg

H

H

C=CC6H13

H

CH=CH2

H

C=CC4H9

H

C4H9

H

C=CC4H9

H

Br

HC4H9Li

Pd(PPh3)4

Pd(PPh3)4

+

+

(75%)

(63%)

Kumada coupling

Organozinc compounds (Negishi coupling)

ZnCl

CH3

NO2Br

CH3CH3

NO2

Pd(PPh3)4+

(78%)

Pd(PPh3)4CH2=CHCH2CH2ZnCl C=C

H

I

(CH2)3CH3

CH3+ C=C

H

CH2=CHCH2CH2

(CH2)3CH3

CH3

(81%)

C=CC2H5

Ph

Ph

BrPd(PPh3)4+ ZnCl C=C

C2H5

Ph

Ph

OMe

(84%)

MeO

SYNTHESIS September 1992Palladium-Catalysed Reactions of Organotin CompoundsTetence N.MitchellFachbereich Chemli,Universitāt Dortmund,Posifach 500 500,D-4600 Dortmund 50. GermanyReceived 16 August 1991;revised 12 December 1991

Pd(PPh3)4

+O

SnMe3

t-BuPh2SiO

I

OSiPr-i3

OSiPr-i3Pd(PPh3)4 / THF

OSiPr-i3

OSiPr-i3

Ot-BuPh2SiO

NH

N

N

NH

Br

Br

CO2MeCO2Me

NH

N

N

NH

CO2MeCO2Me

Bu3Sn

85%

90%

C=C

R

H

Pd2+

X

HR'M C=C

R

H

Pd2+

R'

H

C=C

R

H H

R'

MX Pd(0)+ + +

coupling of terminal alkynes with vinyl ro aryl halides

copper acetylide

HC CR CuC CR

R'X Pd R'Pd X

R'Pd R'C Pd

Cu(I)

R3N

+

+0

110

CR

C CR

11

Sonogashira Coupling

synthesis of enynes

O

Br

BrEtO Et3N

(Ph3P)2PdCl2, CuI,

SiMe3 O

SiMe3

EtO

SiMe3(88%)

N

O

PhO

OH

O

Cl

SiMe3

Ph(OAc)2, PPh3

CuI, nBuNH2 (88%)

N

O

PhO

OH

O

SiMe3

Skeleton Reanangement

R3P NiCl

Ph

R3P

(CH3)2CHMgX R3P Ni

Ph

CH

CH3

CH3R3P

R3P

R3P

Ni

HPh

CH2

CH

CH3secondary

nickel - alkene complex

primary

PhCH2CH2CH3

+ R3P Ni

Ph

R3P

CH2CH2CH3