carbon nucleophiles : organometallics of li, mg etc. 1. cyanide :well known 1 carbon unit 2....

Carbon Nucleophiles : Organometallics of Li, Mg etc.

1. Cyanide : Well known 1 carbon unit

2. Acetylides : pKa = 25

HHNa

NaHR X

RH

Requires polar solvent to solubilize CN-

LiCN – THF NaCN – DMSOKCN – need 18-C-6

HREtMgBr

MgBrR

HRR'Li

LiR

3. Grignard Reagent : R-MgX

a. preparation

R X + Mgether

additivesR MgX

Additives : mechanical force, I2, MeI, BrCH2CH2Br to activate the surface of heterogeneous reaction.Reactive Mg ( Rieke Mg) : prepared from MgX2 + K --- black Mg powder

Reactivity of Halides : RI > RBr > RClradical intermediates through electron transferLoses stereochemistry !!

b. structure

2 RMgX R2Mg + MgX2

X

Mg

X

Mg RR

Solvent dependent, sometimes temp. dependent

3. Grignard Reagent : R-MgX

c. reaction

RMgX + R' X R' R

Usually not so good reaction except for MeI or BnIWith CuI or LiCuCl4 cat. Reaction works

Self condensation is called Wurtz coupling – problem during Grignard formation

RMgX +O OHR

RMgX +R R'

OR' CN

3. Grignard Reagent : R-MgX

c. reaction

Reduction of ketones

O MgBrOH

MgBrL O

S+

L OH

S

Very low e.e.

OH

MgL

S

4. Alkyl lithium

a. generation

+i) R X + 2Li R Li Li X

Usually contains Na(0.02%)Accelerates reaction

Cl : ppt.Br : solubleI : cannot formExcept MeI, ArI

ii) Metal-Halogen exchange rxn.

+Ar X + n-BuLi Ar Li n-Bu X

++ 2 t-BuLiBr Li + + LiBr

Sometimes faster than acid-base reaction

O O

C6H13 SPhLi-naphthalenide

O O

C6H13 Li

- 78oC O O

C6H13 Li

- 20oC

4. Alkyl lithium

a. generation

iii) Transmetallation – gives clean generation

+ 4 PhLiSn Li + Ph4Sn4

4

+ PhLi + Ph4SnSnPh3 Li

Too reactive to form by other ways

Too slow to form by other ways

iv) Metal-Hydrogen Exchange

EtLi + EtH +

Li

a. generation

iv) Metal-Hydrogen Exchange – directed metallation

+ BuLi

OMe OMe

Li O- inductive effect

+ BuLi

O NEt2 O NEt2

LiTMEDA

+ s-BuLiTMEDA

N

O Ot-Bu

N

O Ot-Bu

Li

through chelation

b. structure

Tetramer in Solid state

Me

Me Li

Li Me

Li

Li

In solution : monomer to hexamer depending on solvents, salts, additives

Reactivity : less aggregate, more reactive

c. reactions

Similar reactivity to Grignard for RX, carbonyls, nitriles

Often times act as base rather than nucleophile

Li

TMEDA

room temp. Li

Unusual reaction

JACS 1989, 111, 765

Cf. MgBr

MgBr

c. reactions

+ R'LiRCOOLiR R'

OLiOLi H2O

R R'

O

Quenching excess R’Li is important !

N

O

OMe

OMe

+ Li

O

OMe

N

O

OMe

OMe

Li

via

Weinreb amide

Asymmetric synthesis

+ MeLiH3C CHO

H NBn2

H3C

H NBn2

OH

H3C

H NBn2

OH

+

91 : 9

H

Bn2N

MeO

H

Me-Li Felkin-Anh Model : Chem. Rev. 1191 (’99)

S

L

MO

H

Nu:

+ BuMgBrC7H15

H OMOM

C7H15

H OMOM

HO

C7H15

H OMOM

HO

+

99 : 1O

BuBu

C7H15

H

OMOMO

H

BrMg-Bu Mg2+

Chelation control

Asymmetric synthesis

N

MeO

BnO

N

t-BuO

t-BuLiN

MeO

BnO

N

Ot-Bu

Li

N

O

O

Ph

O

PhMgBr

CuBr(cat.)N

O

O

Ph

OPh

98 : 2

A.I. Myers, Het. 295 (’89)

ArCH2BrN

MeO

BnO

N

t-BuO

CH2Ar

97% e.e.

JOC, 766 (’93)

MeMgBr

O

O

O

H

*RO

O

OH

H3C H

*RO

O

OH

H3C H

+

99.7 : 0.3CC, 988 (’82)

5. Organozinc (R2Zn) : d10, low reactivity: less nucleophilic, less basic

a. generation

R MgCl + ZnCl2 R2Zn + MgCl2

R X + Zn R2Zn + ZnCl2

b. reactions

Reformatsky reaction

+ ZnY

X

O

Y

OZn

O

Y

O

OH

R2Zn +

ONo Reaction

more selectivehigh functional group tolerance

lewis acid

R

OH

MgCl2TMSClBF3TiCl4

Synthesis, 571(’89)

b. reactions

R2Zn +

OR

OH

activator N N N OH N SH

activator

stereoselective addition to carbonyl with chiral activator

EtOOCBr Zn

EtOOCZnBr

functional group tolerability in the reagent

NMe2

OHNH

Ph

Ph

OH

NHTf

NHTf

Asymmetric reaction

NCHO

+ Et2Zn

OH

2 mol%

OH

99% e.e.

Noyori : ACIE 1991, 30,49

N

O Zn

R

Zn

R R

OH

R'

Model of catalyst – not real

Works well with aryl aldehydesWith alkyl aldehydes e.e. are not high

Asymmetric amplification : nonlinear effect

NCHO

+ Et2Zn

OH

8 mol%

OH

98% e.e.100% e.e.

95% e.e.15% e.e.

catalyst % e.e.

product% e.e.

Dimeric form of Cataylists are usuallyResponsible for the effect

Asymmetric amplification : nonlinear effect – mechanisms proposed

SS RR

S R

SR

+

Khomo

Khetero

catalytic

cycle

catalytic

cycle

Khetero > Khomo

Dimeric form of Cataylists are usually responsible for the effect

Noyori, Kitamura, JACS, 9800 (’98)

SS RR

SR

Kdimer

catalytic

cycle

catalytic

cycle

catalytic

cycle

Blackmond, JACS, 10103 (’01)

N

N

CHO

+ i-Pr2Zn N

N

OH

(20 mol%)

85% e.e.Ph

NHH

chiral initiator

C.P.L.racemic mixture

0.1% e.e.

Asymmetric auto catalyst : origin of chirality in nature (?)

N

N

CHO

+ i-Pr2Zn N

N

OH

(20 mol%)

N

N

OH

5% e.e. 39% e.e.

39% e.e. 76% e.e.76% e.e. 85% e.e.

85% e.e. 89% e.e.Nature 1995, 378, 767

JACS 1998,120, 12157ACIE 2000, 39, 1510

Homework

Chapter 7 : 1, 4, 5, 6, 8, 14

Due : May, 18