organolithiums - preparation and reactivity lithium ... · organolithiums - preparation and...

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Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the equilibrium varies With the stability of the carbanion intermediate: RLi + R'X RX + R'Li Li + I Li + I Stability: sp>sp 2 >sp 3 Alkyl iodides are more reactive than bromides and chlorides are inert. Li 2 + I Li + I tert-butyllithium tert-butyllithium H + + LiI Br OEt 1.1 BuLi Li OEt JOC, 1978, 1595 S t e r e o s p e c i f i c i t y : Br 1. 2t-BuLi Br 2. 77% TL, 1986, 4839

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Page 1: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

Organolithiums - Preparation and ReactivityLithium-Halogen exchange is an equilibrium process, and the position of the equilibrium variesWith the stability of the carbanion intermediate:

RLi + R'X RX + R'Li

Li +I

Li

+ I

Stability: sp>sp2>sp3

Alkyl iodides are more reactive than bromides and chlorides are inert.

Li2 +I

Li+

I

tert-butyllithium tert-butyllithium

H ++ LiI

Br OEt

1.1 BuLi

Li OEt

JOC, 1978, 1595

Stereospecificity:

Br

1. 2t-BuLi

Br

2.

77%

TL, 1986, 4839

Page 2: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

Organolithiums - Preparation and Reactivity

I 1. 2t-BuLi

2.PhCHO

OH

JOC, 1990, 5404

Note: lithium-halogen exchange is faster than the rate of proton transfer!

I + CH3OH2 eq. tBuLi

H

93%

TL, 1986, 1861

O

NOMe

OMe

MeO

MeO

I

2 eq. tBuLi

OMe

MeO

MeO

O64%

TL, 1992, 5431

Mechanism of lithium-halogen exchange: "ate" complexation

Li I+ I

Li+

BuI

Bu

JACS, 1985, 4101

Less reactive

Page 3: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

Directed Ortho Metallation

Chem Rev. 1990, 879DMG

RLiDMG

Li

E+DMG

E

DMG's:

Ar

O

NR2 ArO

O

NR2

O

NAr

ArOCH3

Ar N Ar

O OCH3 Ar–CF3 Ar–Cl

RN

NRAr

OR

ORAr

Ar–O-

ArCH3O-

Relative Rates of directed metalation:

SO2NR2, CONR, CH2NR>OCH3>CF3, F, NR2

ArN(CH3)2

ArCH2N(CH3)2

ArSO2tBu

CONR> CONR2>O

N

> OCH3 > Cl

Protecting groups serving as DMG's

OR

ORAr

O

NAr

JOC, 1982, 34Tet, 1983, 1983

Cl

O N1. 3 eq. BuLi2. MeI

THF, -78°C

Cl

O N

CH3

Page 4: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

Directed Ortho Metallation

1.sec-BuLi2. MeI

THF, -78°C

O

NEt2

MeO

O

NEt2

MeO

CH3

Lithiation occurs ortho to the better directing group:

Aldehydes can be transiently protected:

O

H

N N

Li

THF, -20°C

OLi

N

NMe2

1.n-BuLi

2. MeI

THF, -78°C

3. H3O+

JOC, 1988, 7175

O

H

CH3ClCl CH3

Cl

Metalation of vinyl ethers and heterocycles: JOC, 1984, 1078

OCH3

O OH H H NMe

H

Acyl Anion Equivalent:

OCH3

H

1. t-BuLi

O

2.

LiOOCH3

H3O+

HOO

JACS, 1974, 7125

Page 5: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

1.sec-BuLiTMEDA, -78°C

2. warm to rt

Carbamate directing groups can rearrange upon warming:

O

O

O

O

NEt2

O

O

OH O

NEt2

1.sec-BuLiTMEDA, -78°C

2. PhCHO, -78°C

O

O

O

O

Et2N

Ph

OH

JACS, 1989, 4829

Directed Ortho Metallation

Page 6: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

Organocuprates

ORMgXor RLi

HO R

1,2 addition

O

RMgXcat. Cu(I)

OM

R

O

R

1,4-addition

Stoichiometric organocuprates:

MeLi + CuIEt2O

MeCu + LiI

MeLi

Me––Cu––Me Li+

"ate" complex

Cuprates other than vinyl, phenyl, or methyl are subject to !-Hydridr elimination;must be handled at or below -40°C

Cu

H R

R'

R––Cu––H +

H R

Page 7: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

Organocuprates

Ease of ligand transfer:

> Ph–– > Me > Et >>PhS, R2N, RC C

Dummy ligands; non-transferable

Order of reactivity of Substrates:

O

>O

OR

, N

O

Me2CuLi

O

Me

O

OMeMe2CuLi

BF3•OEt2

O OMe

Me

unreactive substrates will react if Lewis acids are added to activate the substratetoward nucleophilic addition

JACS, 1977, 8068

JACS, 1978, 3240

Regiospecific Enolate Trap

O

R2CuLi

TMSClTMSO

R

MeLi

LiO

R

JACS, 1974, 7114

Page 8: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

Organocuprates

Addition to acetylenes:

R' CO2R

Me2CuLiR' CO2R

Me Cu

stable at -100°C

cis-addition

0°C R'

CO2RMe

Cu

isomerize

Alkenyl Coppers can be trapped:

R' CO2R

Me Cu

E+ R' CO2R

Me EH3O+, NBS

Leaving Group Displacement:

X

O

Me2CuLiX

OLi Me

Me

O

-X-

X= SPh, Cl, Br, OAc, but not :ORTL, 1973, 3817

JACS, 1969, 1851TL, 1974, 925

mechanism: cis addition, trans elimination, net retention of stereochemistry

Ketone Synthesis

O Cl (t-Bu)2CuLi O

no epimerization of axial carbonyl group

Page 9: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

Organocuprates

Addition to terminal alkynes: synthesis of trans or trisubstituted alkenes

R' H

R'Cu R' H

Cu R'cis-addition

H+

R' H

H R'

E+

R' H

E R'Mechanism of cuprate 1,4 addition

Me2CuLi +O SET

Me2Cu• Li+ +

O• O-

radical anion intermediate - short-livedEvidence:

O

OTos

Me2CuLi

•O

OTos

O

H3O+

trap the radical anion intermediate

Possible mechanism

TL, 1975, 187

O

Li

O

Li(CuMe2)n

LiO

CuMe2Cu(III)

oxidativeaddition

reductive elimination

LiO

JACS, 1989, 8276TL 1985, 6015

Higher Order Cuprates: More reactive toward a range of substrates:

MeLi + CuCN ==> MeCu-CN Li+ (Only Me transferred. CN is a dummy ligand)

2RLi + CuCN ==> R2Cu(CN) Li2

Page 10: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

OrganoZincsOrganozinc reagents are low reactive organometallics. Et2Zn doesn’t add to benzaldehydeat room temperature, but the addition of TMEDA (a diamine) promotes addition at RT

O

H + Et2Zn

5 mol% TMEDA OH

racemic

ordinarily in the presence of a diamine

ZnMe Me

180°

Zn

H3C

H3C

NR2

NR2

145°increase in Zn-C bond length (1.95Å to 1.98Å)and decrease in bond angle makes methyls more nucleophilic in the presence of the coordinating diamine

Noyori developed the first highly enantioselective addition to aldehydes utilizing the chiral amino alcohol(-)-DAIB as a catalyst

N(CH3)2

OH

-DAIB

R

O

H

+ R2'Zn2 mol% (-) DAIB

R

OH

R'

R R' % yield ee JACS, 1986, 6071

Ph Et 97 98Ph Me 59 91PhCH2CH2 Et 80 90C6H13 Et 81 61

An example of Ligand-AcceleratedCatalysis

Page 11: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

Enantioselective addition of organozincs to aldehydes

No alkylation occure when the ratio of ligand to Et2Zn was 1:1. Catalyticquantities of ligand were required. Proposed transition state assembly:

N

O

Zn

R

Zn

O

R

H

PhR

TL, 1987, 5237JOC, 1987, 4142

a dimeric zinc species containing only one chiral ligand

dimeric zinc species with two chiral ligands are unreactive

Prep of the Zinc reagents:

2 MeLi + ZnBr2 Me2Zn + LiBra.

b. 1. Et2BH

2. Et2Zn

Zn

2

Ic. Et2Zn,

cat CuI

Zn

2

Zinc-iodine exchange

hydroboration/transmetallation

transmetallation JOC, 1992, 1956

JOC, 1996, 8229

JOC, 1996, 7473

Page 12: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

Enantioselective addition of organozincs to aldehydes

O

H

NHTf

NHTf

Zn(pent)2

Ti(OiPr)4

20mol%

OH

88%, 98%ee

JACS, 1997, 9130

ArylZinc additions:

R

O

H

Ph2Zn

Et2Zn

10 mol% cat.R

OH

Fe N

O

OH

PhPh

cat

R % yield % ee

i-Pr 75 91

tBu 68 94

PhCH2 82 83

PhCH=CH 97 90

ACIEE, 2000, 3465

Prep of Alkenylzinc reagents: alkenyl and aryl ligands are transferred much faster than alkyl from zinctherefore, this allows the use of mixed alkyl alkenyl zinc species.

RHB(Cy)2 R

B(Cy)2

Et2ZnR

ZnEt

RCp2ZrHCl R

ZrCp2Cl

Me2ZnR

ZnMe

Page 13: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

Enantioselective addition of organozincs to aldehydes

Alkenylzinc additions:

R

O

H 1-5 mol% (-)-DAIB R

OH

R R' % ee

Ph Bu 96

Et C6H13 86

C6H5 t-Bu 98

R'

ZnEt

R'

Helv. Chim. Acta, 1992, 170

TMS

I

1. t-BuLi, ZnBr2

2. NMe2H3C

OLiPh

3. ArCHO

TMS

OH

Ar

95% eeJACS, 2002, 773.

OHO

H HB(Cy)2

Et2Zn,

1mol% (+)-DAIBJACS 1993, 1593

Page 14: Organolithiums - Preparation and Reactivity Lithium ... · Organolithiums - Preparation and Reactivity Lithium-Halogen exchange is an equilibrium process, and the position of the

Alkynylzinc Additions to aldehydes

Alkenylzinc additions:

R

O

H Zn(OTf)2, Et3N

cat.

R

OH

R R' yield % % ee

C5H11 Ph 90 97

i-Pr Ph 96 92

Ph CH2CH2Ph 67 89

R'

H R'NMe2H3C

OHPh

=cat.

in situ-generated

zinc acetylide; reaction can

be rendered catalytic

at elevated temperatures

using 20mol% Zn(OTf)2

JACS, 2000, 1806