Chapter 4 Formation of carbon-carbon bonds: reaction of organometallic compou

nds

Topics:

Grignard reagents and electrophiles

Other organometallic reagents and electrophiles

Reactions of nucleophiles derived from alk-1-ynes

Review

Worked example

4.1 Grignard reagents and electrophiles

4.1.1 Alkylation

4.1.2 Reactions with carbonyl compounds

4.1.3 Reactions with imine and cyano compounds

4.1.4 Reactions with α,β-unsaturated carbonyl comp

ounds

4.1.5 Alkenyl and alkynyl Grignard reagents

4.1.1 Alkylation

XMg R `R Y R R`

XMg RO R CH2CH2O

-+MgX H+ R CH2CH3OH

For example

MgIn I

m n m

MgBrC2H5OSO2OC2H5

C2H5

PhMgBr

ClCH2

Cl

PhCH2

Cl

PhCH2CH2OHO THFPhMgBr

4.1.2 Reactions with carbonyl compounds

XMg R O

R1

R2

OH

R1

R2

RO-+MgX

R1

R2

R

For example

MgCl HCHOCH2OH

CH3CHO

MgBr

OH

CH3COCH3

MgBr

OH

XMg R O

R1

YO

R1

R

O-+MgX

R1

Y

R

RMgX

OH

R1

R

R

For example

2CH3MgI

2CH3MgI

PhCOCl

(PhCO)2OOH

Ph

CH3

CH3

OH

MgBrHCOOC2H5

OH

2CH3MgI

O

OC2H5

RXMg

RMgXCH2O

RCH2OHO

RCH2CH2OH

primary

R'C

HO

CH OHR'

R

HC

O2 R

'

CH OHR

R

O

R'

R'CH-CH2R

OH

secondary

R'CO 2

R''

HOR

R'R

R'COR''

HOR

R'R"

tertiary

Synthesis of Alcohol by Grignard Reaction

MgBr

CO2

COOH

4.1.4 Reactions with compounds containing C≡N

MgBrN

CN

N

C

O

4.1.4 Reactions with α,β-unsaturated carbonyl compounds

OXMg-R

O-MgX+

C

R

OH

C

R

O-MgX+C

RH

OC

R

4.2 Other organometallic reagents and electrophiles

4.2.1 Organolithium reagents

more reactive and less bulkyl

4.2.2 Organozinc and organocadmium reagents

less reactive and used only for special purposes

4.2.3 Organocopper (I) reagents

less reactive and more selectivity

4.2.1 Organolithium reagents

PreparationRBr + 2Li RLi + LiBrRBr + R’Li RLi + R’Br

(Generally R’ refers to n-BuLi)

Organolithium reagents react similarly with Grignard reag

ents and more efficiently in certain cases. With α,β-unsatur

ated carbonyl compounds they show a greater preference f

or addition at the carbonyl carbon.

PhCOO-Li+PhLi PhCOPh

PhCH=CHCOO-Li+CH3Li PhCH=CHCOCH3

Li

OCH3H3CO

H N

O

Ph

CHO

OCH3H3CO

4.2.2 Organozinc and organocadmium reagents

Organozinc reagents (Reformatsky reaction)

Note: Reactions with α,β-unsaturated carbonyl compounds give preferentially the 1,2-addition products.

RCH(Br)CO2R1 + Zn RCH(ZnBr)CO2R1 or RHC C

O-+ZnBr

OR1

R2COR3

C C

CO2R1

HR

BrZn+-O

R2R3

C C

CO2R1

HR

HO

R2R3

H+

(Work-up)

Organocadmium reagents

• Preparation

2RMgX + CdCl2 R2Cd

• Used especially for the conversion of acyl chlorides into ketones

R2Cd + 2R’COCl 2RCOR’

e.g. [CH3(CH2)3]2Cd + ClCH2COCl CH3(CH2)3COCH2Cl (51%)

[(CH3)2CHCH2CH2]2Cd + ClCO(CH2)2CO2CH3

(CH3)2CH(CH2)2CO(CH2)2CO2CH3 (73%)

4.2.3 Organocopper (I) reagents

• Preparation

RMgX + CuX RCu + MgX2

RLi + CuX RCu + LiX

RLi + RCu R2CuLi

2R-Li + CuX R2CuLi + LiX

• Ponits of synthetic importance:

– Displacement of halogens is particularly facile.

– Acyl halides are the only class of carbonyl compound to react with.

– When reacting with α,β-unsaturated carbonyl compounds give 1,4-ad

dition products.

– Coupling reactions occur when heated.

4.3 Reactions of nucleophiles derived from alk-1-ynes

4.3.1 Sodium, lithium and magnesium derivatives

They can undergo the usuall range of reactions with electrophiles:

• Alkylation

• Reaction with carbonyl compounds

RC CH

Na+-NH2

RLi, ether

R'MgX

RC CMgX

RC CNa

RC CLi

4.3.2 Alkynylcopper(I) compounds

• Preparation

• Ponits of synthetic importance:

– Displacement of halogens from’unreactive’ positions.

– Conversion of acyl halide into ketone

– Coupling reactions giving conjugated diynes.

RC CH + CuCl RC CCu + 2HCl

OHPh

MeEt EtMgX + PhCOMe

synthons: Et

OHPh

Me

or Et-

OHPh

Me+

Synthetic equivalents

R-R’ R-; R’+

R’-Y (Y = X (halides), OTs (sulfonates))RCH2CH2OH R-; +CH2CH2OH

RCO2H R-; +CO2H

CO2

O

CCH

O

RR-;

CCH

O+

CC O

4.4 Review

Synthetic equivalents

Nucleophilic

SynthonsR- RMgX, RLi, R2Cd, RCu, R2CuLi

Electrophilic

Synthons

R+ RCl, RBr, RI, ROSO2R1

RC+=O RCOCl, (RCO)2O, RCO2R1,RCN

HC+=O HCO2R1,

HC+=O | OH

CO2

C+H2OH HCHO

RC+HOH RCHO

R2C+OH R2CO+CH2CH2OH

O

4.5 Worked example

OH

PhCH2+ + CHCH2CH3

OH

Synthetic equivalent

PhCH2+

PhCH2- + CHCH2CH3

OH

+

OH

+CH3CH2CHO

PhCH2- PhCH2MgX

PhCH2Br

CHCH2CH3

OH

PhCH2CH+

OH

+-CH2CH3 -CH2CH3 EtMgX

PhCH2CH-

OH

++CH2CH3

+CH2CH3EtBr

PhCH2CH+

OH

PhCH2CHO

1-phenyl-butan-2-ol

Two synthetic routes have therefor emerged:

PhCH2MgBr + CH3CH2CHO and PhCH2CHO + BrMgCH2CH3

O

O

O

Pentadecan-4-one

+

O

-

-

O

+

+

O

-

+

O

-

3-Phenyl-butyric acid methyl ester

O

O

O

O

+-

CuLi

O

O

+

Cl

O

O

O

O

OH

O

MgBr

CO2

O

O

CH3OH

H+

Br

Br

O

O

methyl cinnmate

O

O

O

O

CH3-

O

O

O

OPh-

O

O

methyl crotonate

pent-3-yn-1-ol

OH

Summary

Grignard reagents, RMgX, are strongly nucleopholic, I.e.

they act as synthetic equivalents of the synthon R-.

They are alkylated by halogenoalkanes, they undergo addition to the carbonyl group

of aldehydes and ketones, they react with acyl halides, anhydrides and esters giving

first ketones and thence tertiary alcohols, with carbon dioxide giving carboxylic aci

ds, and with tertiary amides, orthoesters and nitriles giving , after hydrolysis, carbon

yl compounds (aldehydes or ketones).

Summary

With α,β-unsaturated carbonyl compounds, nucleophilic addition to the ca

rbonyl group and conjugate addition (at the β-carbon) are both observed, t

he former usually predominating. Grignard reagents are also strong bases

and are protonated even by weak acids such as water, alcohols and alk-1-y

nes.

Organolithium reagents react similarly but are even stronger nucleophiles an

d stronger bases. With α,β-unsaturated carbonyl compounds they show a greater

preference for addition at the carbonyl carbon.

Organozinc and organocadmium reagents are less reactive nucleophiles than

Grignard reagents but are used nowadays only for certain specific purposed.

Organocopper(I) reagents (Rcu or R2CuLi), although also synthetic equivalent

s of the synthon R-, show a different pattern of reactivity: they readily undergo al

kylation, acylation and conjugate addition but do not undergo addition to carbony

l groups.

Deprotonation of alk-1-ynes (using a strong base such as sodamide or

a Grignard reagent) furnishes useful nucleophiles which undergo the exp

ected reactions, e.g. alkylation and reaction with carbonyl compounds. Al

kynyl-copper(I) reagents react smilarly to alkyl- and aryl-copper reagents

but they also undergo oxidative coupling to give conjugated diynes.

Some rules for the disconnection of target molecules, tabulated lists o

f synthetic equivalents for various synthons and one worked example are

includeded at the end of the chapter.