NPTEL – Chemistry – Principles of Organic Synthesis

Lecture 5

3.0 Organometallic Reagents

Organometallic compounds are those compounds which have metal-carbon bond. Due to
the significant difference in electronegativity between metals and carbon, they are highly
polar in nature. However, this definition is not quite explicit as many reagents deemed to
be organometallic in nature do not possess a metal carbon bond. Wilkinson catalyst,
(RhCl2(PPh3)2), a popular organometallic catalyst for hydrogenation reaction does not
possess a metal–carbon bond. Thus, the above definition may be modified to include
compounds containing metal- electronegative atom bonds in the gambit of organometallic
compounds.

Li C N O

0.98 2.55 3.04 3.44

Na Mg Al Si P

0.93 1.31 1.61 1.9 2.19

K Fe Co Ni Cu Zn

0.82 1.83 1.88 1.91 1.9 1.65

Ru Rh Pd Cd

2.2 2.28 2.2 1.69

Os Ir Pt Hg

2.2 2.2 2.28 2.0

Fig 1: Elements commonly involved in formation of organometallic compounds. (Elements highlighted in blue are the source
of most common organometallic reagents used for organic synthesis)

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

R 2.55 3.44 R 2.55 0.98

2s C O
H C Li
H H

n
RLi attacks here This carbanionic carbon
sp3 attacks RCHO

A.O of Li M.O of Li-C bond A.O of C

Fig 2 : M.O diagram of C-Li bond showing the high degree of polarization.

The high polarity of the metal-carbon bond is responsible for the high ionic nature of the
organometallic compounds (Fig 2). As such these reactions mostly involve nucleophilic
attack of the carbanion on the electrophillic center of an organic molecule.

TRIVIA
The first organometallic compound was synthesized by French Chemist Louis Claude
Cadet de Gassicourt in 1760 by the reaction of potassium acetate with arsenic trioxide.
This red coloured liquid is called Cadet’s Fuming Liquid in his honour.

4 CH3COOK + As2O3 → As2(CH3)4O + 4 K2CO3 + CO2

3.1 Classification of Organometallic Compounds

Organometallic compounds may be classified in different ways. They may be classified
according to the type of metal-carbon bond or according to the metal center involved in
these compounds. For our convenience we will follow the latter classification throughout
this text.

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3.1.1 Grignard Reagents

Grignard reagents are organometallic compounds having Mg-C bond. Magnesium can
form two covalent bonds with carbon. Of the various organomagnesium compounds
possible, organomagnesium halides and to a lesser extent dialkyl magnesium compounds
are widely used for synthesis. Although the Grignard reagents are usually formulated as
RMgX, but in reality they are a mixture of a variety of species. The ratio of the species in
solution varies with the organic group, the halogen, the solvent, the concentration and the
temperature. It is believed that in case of organomagnesium chlorides (RMgCl) in diethyl
ether, the predominant species over a wide range of concentrations is a solvated, halogen-
bridged dimer 1. The degree of association varies as the halide is changed to Br or I.
Et2O X R
Mg Mg
R X OEt2

However, in case of THF, due to the highly coordinating nature of the solvent, there is a
lesser degree of association. Therefore, monomeric species dominate in THF, however,
there are significant concentrations of R2Mg, MgX2 and RMgX in equilibirium.

R2Mg + MgX2 2RMgX

3.1.1.1 Addition of Grignard Reagents to Carbonyl Groups

The addition of Grignard reagents to carbonyl group is one of the most important
methods for carbon-carbon bond formation. Though the overall reaction is quite simple
but it is highly susceptible to a number of side reactions. The reactivity of Grignard
reagents towards different carbonyl group containing compounds also varies thus giving
rise to different end products depending on reactants (Scheme 1).

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R-H

OH H+/H2O
R RCH2OH
O
HCHO
R1
O O
CO2 H HR
R OH RMgX OH
R1
R1
R1 C N O
R1 R2
O
O R2O R1
HO R
R R1 R2
OH

R R1
R

Scheme 1

The mechanism of this reaction is usually depicted to consist of the following steps-

 Complexation of the organomagnesium species with the substrate (Scheme 2).

R1 R1
O O
R2 R2 X
Mg
+
R
R MgX OEt2

Scheme 2

 The next step involves nucleophilic attack of organic moiety of Grignard reagent
on the electron deficient carbon of carbonyl group via a molecular complex
(Scheme 3).

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R1
O R1 O R
2 R2 Mg R1
R X
Mg O Mg R + MgX2
R X R2
Mg R
R
OEt2 X

Scheme 3

 The intermediate formed in the above step is hydrolyzed to give a tertiary alcohol.
However, if the carbonyl group is attached with a leaving group (i.e., if R1= OR)
then the tetrahedral adduct can break down to regenerate a C=O group that
undergoes a fast second addition step (Scheme 4).

O OMgX O OH
R1MgX
R1MgX OEt
R OEt + R1 R R R1 R R1
R1
Scheme 4

However, a number of methods have been devised to stop the reaction at the aldehyde or
ketone stage. Such protocols involve the formation of a masked carbonyl compound,
which releases the desired compound on hydrolysis (Scheme 5).

O-+MgX O
O H+/H2O
+ RMgX Me2N R R H
Me2N H

N-+MgX O
N
C
R R
+ RMgX

Scheme 5

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In case of reaction of Grignard reaction with carbon dioxide, the reaction stops at the
carboxylate (RCO2-) stage as it is resistant to further nucleophilic attack (Scheme 6)

O O
MgX
CO2 O- +MgX OH
H+/H2O

Inert to further
nucleophillic attack

Scheme 6

Grignard reactions are prone to undergo side reactions. The reaction of a sterically
hindered ketone with a Grignard reagent having a β-H shows a tendency towards
reduction of the carbonyl group (Scheme 7).

O H
i
Pr OH
Me Me Me
iPr Me Me
+
Me Me Me MgBr O Me +
Me Mg Me Me
Br
Scheme 7

Examples:

Me O
Me
OMe Et2O
1. + MgBr
OH

40%

P. A. Wender, T. M. Dore, M. A. Delong, Tetrahedron Lett. 1996, 37, 7687.

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MeO O
MeO O

MgBr
2. HO
O OSiMe2t-Bu
OSiMe2t-Bu
OMe
OMe
90%

S. Hanessian, J. Pan, A. Carnell, H. Bouchard, L. Lesage, J. Org. Chem. 1997, 62, 465.

Me PhMgBr
3. Me O
O Me O Me
O OH
O Ph
94% major isomer

W. F. Bailey, D. P. Reed, D. R. Clark, G. N. Kapur, Org. Lett. 2001, 3, 1865.

O O
O O
Me
MgBr OH HO Ph
4. Ph Ph OMe
OMe +
Me
Me Me
37% 61%

T. Uyehara, T. Marayama, K. Sakai, M. Ueno, T. Sato, Tetrahedron Lett. 1996, 37, 7295.

Bu
1.t-BuMgCl Cl Bu
5. HO CN O CN O CN HO CN
2. BuMgCl Mg Mg 81%

F. F. Fleming, Q. Wang, Z. Zhang, O. W. Steward, J. Org. Chem. 2002, 67, 5963.

3.1.2 The Stereochemistry of Grignard Reaction

The stereochemical outcome of Grignard reaction can be predicted on the basis of Cram’s
rule. To apply Cram’s rule we designate the groups on the carbon adjacent to the
carbonyl group as small (S), medium (M) and large (L). The preferred conformation of 2-
phenyl-propanaldehyde has carbonyl group staggered between methyl group (M) and

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hydrogen atom (S). Now according to Cram’s rule, the nucleophilic attack by
phenylmagnesium bromide will take place from the least hindered position between
methyl group and hydrogen atom (Scheme 8).

O
OH
Me H
Nu = PhMgBr Me H
H Nu
H Ph
Ph
Ph
Threo isomer

Scheme 8

In the case of the Grignard addition to chiral substrates that possess a heteroatom in the
α- or β- position, a modification in the application of the Cram’s rule is required. In the
reaction of (S)- 2-methoxy-1-phenylpropanone with methyl magnesium bromide, a cyclic
structure where the methoxy group is synperiplanar to carbonyl group is formed. This
results in the restriction in the freedom of the diasteroselective transition state and thus
the attack takes place from the least hindered side having the methyl and the methoxy
groups (Scheme 9).

Me
Mg
X
O O OH
OMe MeMgBr H OMe H OMe
Ph
Me Ph MeMgBr Ph Me
Me Me
Favoured Chelated Threo isomer
Transition state.

Scheme 9

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3.1.3 Other Uses of Grignard Reagents

Grignard reagents are not only useful reagents for organic transformation but they are
also useful in the synthesis of other useful organometallic reagents such as organosilicon
and organophosphorus reagents. For example, the reaction of Grignard reagents with
SiCl4 and PCl3 gives triphenylphosphine and tetramethylsilane, respectively (Scheme
10)..

PCl3 + 3PhMgBr PPh3 + 3MgBrCl

SiCl4 + 4MeMgBr + 4 MgBrCl

Me4Si
Internal Standard
for NMR

Scheme 10

TRIVIA
Victor Grignard was awarded the Nobel Prize in Chemistry in 1912 for the discovery and
application of organomagnesium reagents.

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Problems

Predict the major products of the following reactions.

MgBr
H+/H2O
1. MeCHO +

Cl

H+/H2O
2. Me O + MeMgCl

O H+/H2O
3. + Excess EtMgBr
EtO OEt

H+/H2O
4. Me 4 + Excess MeMgBr
O
O MgBr

5. EtO OEt
+ H+/H2O
OEt

6. O + H+/H2O
MgBr
MeO N
Me

Text Book

M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, Singapore, 2004.

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Lecture 6

3.3 Organolithium Reagents

Organolithium reagents are one of the most useful nucleophillic reagents in organic
synthesis. They are also highly basic in nature. However, due to their thermal instability
and extremely high reactivity they require elaborate precautions during use. Many
organolithiums are commercially available as dilute solution in hydrocarbon solvents. In
such solvents they are polymeric species with n = 4 to 6. In ethers, however, they are
mostly tetrameric in nature. In the presence of strong donating molecules such as HMPA
and DMPU, the degree of association decreases and they exist as monomeric species.
This leads to an enhancement in their reactivity. Tetrameric structures are based on
distorted cubic structures where the lithium atoms occupy alternate corners of the cube
and the alkyl groups occupy a face of the cube.

3.3.1 Preparation

Organolithium reagents are usually prepared by the reaction of organic halides with
lithium (Scheme 1). The order of reactivity of the organic halides decreases in the
following order RI > RBr > RCl.

R X + 2Li R Li + LiX

Scheme 1

Another route to organolithium compounds is the use of metal halogen exchange

reactions. In these reactions the equilibirium lies to the right if the organic group is able
to accommodate the electron density than the organic species on the left (Scheme 2).

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R Li + R1 X R1 Li + R X

Br Li
Me Me Me Me
+ n-BuLi + n-BuBr

Me Me
Br Li
+ n-BuLi
+ n-BuBr
O O

Scheme 2

The replacement of a hydrogen by a lithium (known as lithiation) can also be used to

generate organolithium species. This reaction is essentially an acid base reaction.
However in case, where there is activation by a coordinating group, the reaction occurs
with considerable ease. This type of activation is particularly helpful in introducing an
ortho substituent to a preexisting coordinating group (Scheme 3).

OMe OMe Li OMe

Et2O, 35° C Li
+ n-BuLi +

major
Et Et
O N O N
Et Et
THF,-78° C Li
+ TMEDA
n-BuLi

O Li
THF, 0° C O-+Li
Me + s-BuLi Me
N N N N
H Me Me
Me Me

Scheme 3

The ortho-directing groups are usually arranged in the following order in order of their
reactivity: SO2NR2 > SO2Ar > CONR2 > oxazolinyl > CONHR > CSNHR, CH2NR2 >
OR > NHAr > SR > CR2O-. .

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3.3.1 Reaction with Carbonyl Compounds

Organolithium reacts with carbonyl compounds as that of the Grignard reagents. In
comparison to Grignard reagents, organolithium reagents are less susceptible to steric
factors and react with hindered ketones to give the corresponding tertiary alcohols
(Scheme 4).

Li H3O+
+
HO
Li-O
O -78 oC

Scheme 4

3.3.2 Reactions with Epoxides

Epoxides react with organolithium reagents to give primary alcohols (as in the case of
Grignard reagents). Use of unsaturated organolithium reagent gives unsaturated alcohols
(Scheme 5).
O Me Li
Me
H3O+ OH
40%
Scheme 5

3.3.3 Reactions with Carbon Dioxide

A major difference between the reactivity of Grignard reagents and organolithium
reagent is observed in their reactivity towards CO2. The reaction of Grignard reagents
with CO2 stops at the carboxylate stage, while in case of organolithium reagents, the
carboxylate ion formed reacts with another equiv of organolithium to generate a ketone
(Scheme 6).
O O-+Li O
Li
O-+ Li MeLi O-+Li Me
+ CO2 Me

Scheme 6

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3.3.4 Reactions with Alkyl Cyanide

As in the case of Grignard reagents, the reactions of organolithium reagents with alkyl
cyanides give imine salts, which undergo hydrolysis in the presence of water to give
ketones (Scheme 7).

R H2O H3O+
R-Li R R
R' N N- L+ NH O
R' R' R'
Scheme 7

3.3.5 Electrophilic Displacement

Reaction of an organic halide with an organometallic compound is known as metal-
halogen exchange reaction is example for electrophilic displacement. This reaction is
useful for the synthesis of vinyl- and phenyl lithium (Scheme 8).
Br + Li Li + Br

Scheme 8

3.3.6 Nucleophilic Displacement

Reactions of alkyl and aryl halides can be reacted with alkyl and aryl lithium reagents to
give hydrocarbons. The reaction of alkyl halides with alkyl lithium takes place by SN2
mechanism. While aryl halides react with aryl lithum via addition-elimination process
(Scheme 9).

Cl Li

+ +

Mechanism
Li
Cl Li
PhH
+ +
LiCl
Protic solvent

Scheme 9

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3.3.7 Reaction with -Unsaturated Carbonyl Compounds

In the case of Grignard reagents, -unsaturated carbonyl compounds undergo reaction

either at 1,2- or 1,4-addition depending on the structure of the carbonyl compound. The
main reason is steric hinderance. While the organolithium reagents undergo reaction
exclusively to give 1,2-addition products (Scheme 10).

PhLi

H+
O Ph OH
Scheme 10

Exclusive formation of 1,4-addition product, however, can be achieved using lithium

dialkylcuprates (Scheme 11).
O O
Me2CuLi

H+ Me
Scheme 11

3.3.7 Deprotonation
The basic nature of organolithiums can also be put to good use in achieving umpolang at
the carbonyl centre of an aldehyde. In this protocol a C=O function is first protected by 1,
3-dithiane and then the proton is removed by an organolithium (Scheme 12).

SH HgCl2/H2O O
O n-BuLi MeI S S
+ S S S S
Ph Me
Ph H R H R R Me
SH

Scheme 12

The stereochemical outcome of the nucleophillic addition of organolithiums is similar to

that of Grignard reaction. It can be predicted on the basis of Cram’s rule.

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3.3.8 Ortholithiation
It is useful because the starting material does not need to have a halogen atom. For
example, in the case of benzyldimethylamine, the nitrogen atom directs attack of the
butyllithium (Scheme 13).

NMe2 NMe2 Me2N Me Me

OH N.. Li
BuLi Li PhCHO H Bu
H+
73%

Scheme 13

Summary of the Reactions of Organolithium Reagents

R-H

OH H+/H2O
R RCH2OH
O
HCHO
R1
O O O
R1Li
CO2 H
R R1 HR
R O-+Li RLi OH
R1
R1
R1 C N O
R1
R2
O
O R2O R1
HO R
R R1 R2
O

R R1

Scheme 14

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Problems

Predict the major products of the following reactions

MeO OTMS n-BuLi
1.

OMe Br
O

2. Me I +
Li

PhLi
3.
N Me O

Me H
O
CN
4. + MeO
Li

OMe
BuLi, Cr(CO)3
5.
Br Me3OBF4
OMe
Me Si Li
Me Me
O
6.

Text Book

J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry, Oxford University

Press, 2001.

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Lecture 7

3.2 Organozinc Reagents

Organozinc reagents are one of the most important of organometallic compounds. The
first instance of an organozinc compound goes back to 1849 when Edward Frankland
discovered that heating a mixture of zinc and ethyl iodide gives highly pyroporric diethyl
zinc. Organozinc compounds in general are sensitive to oxidation, dissolve in a wide
variety of solvents whereas protic solvents cause decomposition. Organozinc compounds
also exhibit the Schlenck equilibrium like Grignard reagents (Scheme 1).

R2Zn + ZnX2 2RZnX

Scheme 1

In terms of reactivity, organozinc compounds are less reactive than Grignard reagents.
This can be explained on the basis of relative position of Mg and Zn in the periodic table.
Since zinc is more electropositive than Mg thus the Zn-C bonds have a higher degree of
covalency compared to the Mg-C bond. In a typical case, the electrons forming the C-Zn
bond reside in two sp hybridized molecular orbitals resulting in linear geometry about the
zinc centre.

3.2.1 Nucleophilic Addition by Organozinc Reagents

Organozinc reagents are less reactive than organomagnesium and organolithium reagents
thereby allowing a higher functional group tolerance. However, this low reactivity means
that they need to be often aided by additives or catalysts.

Reformatsky reaction is one of the most important applications of organozinc reagent

formed in situ. In this reaction zinc, α-haloester and a carbonyl compound react to give β-
hydroxyester. The reaction involves the formation of a zinc enolate which attacks the
carbonyl group (Scheme 2). As the zinc enolate is only weakly basic so the reaction
works even in the presence of highly enolisable carbonyl partner. Sterically hindered
ketones do not pose a problem for this reaction.

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O O OH O
Et2O
+ Br + Zn
R Me EtO R OEt
Me

O-+ZnBr OH O
O
Zn
Br R OEt
EtO EtO Me
R
O
Me
Scheme 2

In case of α,β-unsaturated carbonyl compound the addition takes place regioselectively in

a 1,2 fashion (Scheme 3).
O Me Me OH
CHO O
Br + TBSO
OMe O TBSO
O OMe
Me Me Me
Me

Scheme 3

The combination of Zn/CH2Br2/TiCl4 is known as Lombordo’s reagent which can convert

ketones to methylene group. The reaction is believed to proceed through a dimetalated
intermediate which adds to the ketone (Scheme 4).
CH2Br2 + Zn
BrZn ZnBr
Cl3Ti Cl
O O TiCl3

R1 R2 R1 R2 R1 R2
BrZn
BrZn ZnBr
Scheme 4

Organozinc reagents readily undergo transmetallation thereby making them suitable

candidates to be used in conjunction with transition metal salts. Thus, RZnI reacts with
THF soluble salt CuCN·LiCl to form new copper-zinc reagents which are usually
formulated as RCu(CN)ZnI. The reactivity of this reagent is shown in Scheme 5.

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O RZnI
R O
R R1
R1 R2
O
CuCN.LiCl
R1 Cl
O

R1 R2
OH
R1 X
R1 R RCu(CN)ZnI
R R1
O

R1 H
X R1
R1 Y
NO2
R1
R R1
R Cu R
1
H+/H2O
R
R1 Y R1 Y
R NO2

Scheme 5

3.2.2 Cyclopropanation by Organozinc Reagents

Alkenes may be conveniently converted into cyclopropanes by treatment with methylene
iodide and Zn/Cu couple. This reaction is known as Simmons Smith reaction. The
reactive species is iodomethylzinc iodide (Scheme 6).

CH2I2
Zn/Cu

Scheme 6

Several modifications are available to allow the use of less reactive methylene group
donors like chloroiodomethane. Such methods employ the use of Lewis acids like TiCl 4
or organic reagents like acetyl chloride or trimethylsilyl chloride (Scheme 7). This
reaction is also sensitive to the purity of zinc. Thus electrochemically prepared zinc is
more effective than metallurigically prepared zinc.

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CH2Br2
Zn-Cu
sonication

OH
OH
Et2Zn
ClCH2I
Scheme 7

Simmons Smith reaction is highly stereospecific reaction as it does not involve a carbene
intermediate (:CH2). In case of additional directing groups, the reaction exhibits
considerable stereoselectivity. In Scheme 8, the stereoselectivity of the reaction is
explained by the coordination of zinc to allylic oxygen in the transition state.
Me O
Me O
H
Me O Et2Zn
CH2OTBPDS Me O
H CH2OTBPDS
CH2I2 H
Zn
CH2 X
H
Me O R R= CH2OTBPDS
Me
O
Scheme 8

Other reagents have been developed having aryloxy or acetoxy anions. These reagents
are effective for cyclopropanation of unactivated alkenes. They are prepared by the
reaction of diethyl zinc with a suitable oxyanion precursor such as trifluoroacetic acid
followed by reaction with methylene iodide to generate reagents having formula
ROZnCH2I. The reactivity of the oxyanions are in the order CF3COO- > ArO- > RO-.
3.3.3 Transition Metal Mediated Addition of Organozinc Reagents
As mentioned earlier, organozinc reagents can be used in conjunction with various
transition metal salts which may be added in either stoichiometric amount or catalytic
amount. This transmetallation reaction has been already discussed in the previous section
for copper salts. In this section we will see the effect of Pd, Ni, Fe and Co salts on the
addition of organozinc reagents.
One of the most useful reactions using Co is the carbonylation reaction. Organozinc
reagents when treated CoBr2 generate organocobalt reagents which are stable for several

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hours at low temperature. Carbonylation is now possible by simply bubbling CO through

such a solution (Scheme 9).
Zn, THF CoBr2, Co bubbling O
I ZnI
I 40° C ZnI
THF:NMP
0-40° C
Scheme 9

Addition of cobalt salts in catalytic amount is known for acylation and allylation reaction
of diorganozincs. The reaction occurs in a SN2 fashion but, not by SN2’ fashion, thereby
leading to a complete retention of double bond geometry (Scheme 10).
Me Me

Zn Cat. CoBr2
+ Me 2
Cl THF:NMP C5H11
-10° C
Me Me Me Me
Scheme 10

The reaction between organozinc compound and an organic halide in the presence of
Pd(0) or Ni(0) species is known as Negishi cross-coupling reaction which is one of the
most widely used cross-coupling reactions. The mechanism of this reaction involves
oxidative addition followed by transmetallation with the zinc compound and subsequent
reductive elimination (Scheme 11). This reaction can be applied to highly substituted
substrates. An interesting example of application of Negishi coupling is the synthesis of
hexaferrocenyl benzene (Scheme 12).
Besides Negishi cross-coupling, Ni and Pd salts are also known to catalyze the
cyclization reactions of organozincs via a radical pathway. In these cases, an intermediate
Ni(0) or Pd(0) is formed which initiates a radical chain providing a new zinc derivative
which can further undergo reaction with other electrophiles (Scheme 13).

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cat Ni(acac)2
OAc
I NMP,THF
+ EtO C
AcO Zn 2 -78-35° C
2 CO2Et

AcO

OAc M(II)

CO2Et
M= Ni, Pd
M(0)

Reductive
Elimination
EtO2C

OAc
M
EtO2C
Ac
O

Transmetallation Oxidative
Addition
I
M
Zn
I
Ac
O

EtO2C
Zn
2

Scheme 11
I R
I I Pd2(dba)3 R R
R= Fe
+ R2Zn
THF, 80° C
I I R R
I R
Scheme 12

Bu Bu CuCN.LiCl
Bu
Et2Zn, THF -40 to 0° C
ZnI NO2
PdCl2(dppf) I NO2
I Ph I Ph
-78° C-rt -78 to 0° C
Scheme 13

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Problems

Predict the major product for the following reactions.

O
Zn
+ OMe
1. Ph H Br
H+/H2O
O

O O
SiMe3 + Br Zn
2. Ph OEt

Zn
O TiCl4
Me Br TMEDA
3. n-Bu OMe +
Me Br

O O Zn
(MeO)3B
4. Ph + Br
H OEt

IZnCH2OPiv
5.
TBDMSO CuCN.2LiCl
n-Bu TMSCl,THF
TBDMSO 1N HCl
Li+-O Me
Zn-Cu
CH2I2
6.
H2O
Me
Me

Zn -Cu
Me CH2I2, Et2O
7. HO

Text Book

J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry, Oxford University

Press, 2001.

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NPTEL – Chemistry – Principles of Organic Synthesis

Lecture 8

3.5 Organocopper Reagents

The pioneering work from the Gilman group in 1936 marked the beginning of the era of
organocopper reagents, describing the preparation of mono-organocopper reagents and
their considerable synthetic potential in organic chemistry. The use of copper salts as
catalysts in organometallic reactions has then been become popular. The observation that
catalytic amounts of copper halides favored 1,4-addition over the usually observed 1,2-
addition in the reaction between Grignard reagents and α,β-unsaturated ketones was of
crucial importance for the further development of organocopper reagents as synthetic
tools in organic chemistry (Scheme 1).

O R'MgX O
OH
R'MgX CuX
R R' R
R + H+
R' H

Scheme 1

Organocopper reagents can be prepared by transmetallating the Grignard or

organolithium reagent (Scheme 2).

CuI (Gilman Cuprates)

2RLi R2CuLi + LiI
CuI
2RMgX R2CuMgX + MgXI (Normant Cuprates)

CuCN
2RZnX RCu(CN)ZnX (Knochel Cuprates)
LiCl

Scheme 2

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3.5.1 Reactions with Alkyl or Aryl or vinyl Halides and Tosylates

Alkyl, aryl or vinyl halides and tosylates react with organocuprates to give cross-coupled
products (Scheme 3). The method affords an effective route for the synthesis of
hydrocarbon from two different alkyl, aryl or vinyl halides.

(Me)2CuLi
I

CuLi
2
Br

(Me)2CuLi Me
OTs
S OTBDPS
S OTBDPS Me
Me

Br Me
(Me)2CuLi
BnO O BnO O
O O

Scheme 3

Mechanism
The reaction takes place via oxidative addition followed by reductive elimination
(Scheme 4).

Me Me
X Me2CuLi Cu Me
-MeCu(I)
R R' R R' R R'
-LX reductive elimination
oxidative addition

Scheme 4

3.5.2 Reactions with Acid Chlorides

Acid chlorides react with organocopper reagents to give ketones (Scheme 5).

CuLi O O
O O
2 MeO
MeO Cl

Scheme 5

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3.5.3 Conjugate Addition

Organocopper reagents undergo 1,4-addition to -unsaturated carbonyl compounds.
The reaction can be stereoselective. For example, the less substituted double bond
undergoes reaction from the less hindered side to give stereoselective product (Scheme
6).

Me
Me
Me
Me2CuLi, THF, -78 oC

H+ O
O
91%

Scheme 6

Mechanism
The reaction takes place via copper(III) intermediate (Scheme 7).

OLi.R2CuLi OLi.R2CuLi OH
O R Li R
Me H
(R2CuLi)2 + Me Cu Cu Me Me
Me
R Li R R2Cu R R
O

Scheme 7

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3.5.4 Reactions with Aldehydes and Ketones

Aldehydes readily react with organocuprates to give alcohols (Scheme 8). However,
ketones are less reactive, but their reactivity can be accelerated using
chlorotrimethylsilane.

Me
Me Me
CHO Me2CuLi OH
O O O O
Me
-70 oC Me
anti:syn 30:1

O OTMS
Me 2 n-Bu2CuLi, THF Me

Me3SiCl, -70 oC

Scheme 8

3.5.5 Reactions with Epoxides

Epoxide reacts with organocopper reagents at the least substituted carbon atom to provide
the corresponding alcohol (Scheme 9).

Me2CuLi
O
THF OH

Me
Me Me2CuLi O
O O
O HO
THF
O Me

Scheme 9

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Higher Order Cuprates

The reaction of organolithium reagent with cuprous cyanide yields higher order cuprate
(Scheme 10). Higher order cuprate is more reactive compared to Gilman reagent towards
alkyl halides. For example, (S)-2-bromooctane reacts with EtMeCu(CN)Li at 0 oC to give
(R)-3-methylnonane in 72% yield (Scheme 11).

2 R-Li + CuCN R2Cu(CN)Li2

Scheme 10

H Br EtMeCu(CN)Li2 Et H

THF, 0 oC

Scheme 11

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Examples:

Br Me
Br + Me2CuLi Me

Me
Me
OH
OH + Me2CuLi Me
Me
Me
I
Me
Me Me
HOH2C HOH2C
O OCH2Ph + Me2CuLi OCH2Ph
OH
1,4-addition

+ C7H15 CO2Me C7H15 CO2Me

C7H15 CO2Me Me2CuLi
Me Li Me
Me OAc Me Me
+ Me2CuLi

Reactions involving in situ genarated organocopper species SN2' displacement

OTf
Me

+ CuI,THF
MeMgBr

MeO2C CO2Me
MeO2C CO2Me

cat Li2CuCl4
Br CO2Et + BuMgCl Bu CO2Et
THF,NMP

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3.5.7 Cadiot-Chodkiewicz Coupling

Monosubstituted alkynes reacts with alkynyl halides in the presence of copper(I) salts to
offer unsymmetrical bisacetylenes (Scheme 12).

Cu(I)/base
R + R' X R R'

Scheme 12

Mechanism
Proceeds via oxidative addition followed by reductive elimination (Scheme 13).

:B
R H R R Cu R' X
-H:B
-X oxidative addition
CuX
III
R R' R Cu R'
reductive elimination X

Scheme 13

3.5.6 Glaser (Oxidative Coupling)

Terminal alkynes can also be coupled by oxidative coupling using copper salts in the
presence of molecular oxygen (Scheme 14).

Cu(I), O2, base

R R R

Scheme 14

O
O
O O
Cu(I), O2 H2, Pt
O
O

exaltolide

Scheme 15

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Using this method the synthesis of macrocyclic lactone, exaltolide, that is partly
responsible for the sweet odour of the angelica root, can be accomplished in high yield
(Scheme 15).
Mechanism
Proceeds via radical intermediate (Scheme 16).

:B O2
R H R Cu R . . R' R R
CuX

Scheme 16

Examples:

N CuCl/O2 N N

O O O

U. Fritzsche, S. Hunig, Tetrahedron Lett. 1972, 13, 4831.

OH NH2OH, HCl, CuCl OH

+
EtNH2

J.-P. Gotteland, et al., J. Med. Chem. 1995, 38, 3207.

3.5.6 Castro-Stephens Coupling

The coupling of alkynes with aryl halides employing copper salt in the presence of base
affords aryl acetylenes (Scheme 17).

Cu(I)/base
R + ArX R Ar

Scheme 17

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Mechanism
The reaction takes place via oxidative addition followed by reductive elimination
(Scheme 18).

:B
R H R R Cu Ar-X
-H:B
-X oxidative addition
CuX
III
R Ar R Cu Ar
reductive elimination X

Scheme 18

Examples:

O O

O CuI, PPh3, K2CO3 O

R. Garg, R. S. Coleman, Org. Lett. 2001, 3, 3487.

MeO

NO2 NO2
I MeO
Pyridine
+
Cu
MeO MeO

G. A. Krause, K. Frazier, Tetrahedron Lett. 1978, 19, 3195.

3.6 Organomercury Reagents

Organomercury reagents are usually prepared by the metal exchange reaction between
mercury(II) salt and Grignard reagent or organolithium. Organomercury compounds have
a significant degree of covalency in Hg-C bond. Hence, they are less effective as
nucleophiles compared to Grignard reagent or organolithium. Thus, they do not react
with aldehydes or ketones but they react with acid chlorides in the presence of a Lewis

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acid (Scheme 19). The most significant reaction involving an organomercury reagent is
oxymercuration-demercuration protocol for hydroxylation of alkenes (Scheme 20).
Unlike hydroboration, this reaction follows Markovnikov’s principle. Another application
of these reagents includes Hoffman-Sands reaction where an alkene can be converted to
monobrominated alkanes (Scheme 21).

O O
AlCl3 +
HgCl HgCl R R1
R + R1 Cl R

R1 O

Scheme 19

Hg(OAc)2 OH OH
NaBH4
C3H7 HgOAc Me
H2O C3H7 C3H7

Scheme 20

OMe
Hg(OAc)2 Br2 OMe
AcOHg
CO2Me CO2Me Br
MeOH CO2Me

Scheme 21

TRIVIA
Organomercury compounds are extremely poisonous. They are readily absorbed through
skin and attack the central nervous system causing severe neurological problems. The
Minamata disease in Japan was caused by the release of methyl mercury wastes into the
Minamata Bay which accumulated in fish which were then consumed by humans in the
region.

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Problems

Predict the products of the following reactions

O
Ph2CuLi, TMSCl
1.
Et
H+/H2O

OTs CuLi
2. 2
S OTBDPS
Me

Br
Me2CuLi
3. BnO
O O

OH
CuCl/O2
4.

CHN2 Cu(acac)2
5.
O

OH
O
6.
Hg(II)
TBDMS

Text Book:

J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry, Oxford University

Press, 2001.

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NPTEL – Chemistry – Principles of Organic Synthesis

Lecture 9

3.7 Application in Asymmetric Synthesis

The process of introducing a new chiral centre enantioselectively is referred to as

asymmetric synthesis. It is important because both the enantiomers are not equally
effective for a specific task. In case of dopamine precursor L-DOPA, only the L–isomer
is biologically active. As we have seen, organometallic reagents are nucleophillic in
nature, so if they can be made to add to a prochiral substrate in such a manner that the
addition takes place in only direction or face then, it is possible to synthesize a compound
enantioselectively. This forms the basic principle for asymmetric catalysis using
organometallic reagents. One of the most common ways to achieve this is to use
enantioselective induction using chiral ligands or metal-ligand complexes. In these
reactions, an additional metal species (usually Lewis acid) in catalytic amount may or
may not be needed to obtain this objective.
Some examples of the use of magnesium, lithium and zinc based reagents/catalysts in
asymmetric synthesis follow.
3.7.1 Reactions with Magnesium Reagents
Aldehydes react with allylic Grignard reagents in an enantioselective manner in the
presence of chiral Ti-catalyst to give the corresponding alcohol in < 95% de. This two
step one pot process

O
Ph OH
Ti H
Cl Ti
O O Ph MgCl O O Ph Ph
Ph Ph Me
Ph Ph
Ph Ph Me
-78 °C
95% de
Me Me Me Me

Scheme 1

involves generation of allyltitanium species by transmetallation of allyl Grignard reagents

and then addition to the aldehyde (Scheme 1).

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Magnesium complex derived from Mg(NTf2)2 and chiral bisoxazoline has been used as
chiral Lewis acid for the cycloaddition of diazoester with electron deficient alkenes
(Scheme 2). The resultant product is used as an intermediate for the synthesis of (-)-
manzacidin.

O O O O O
O 30 mol% Mg(NTf2)2 Me
N 30 mol% L* N OEt
+ EtO
N Bn Me N HN N
Me N2 DCM, -20 oC, 48 h
Me Me Me Bn
97% yield, 99% ee
O O

N N
L*
O
Me
CO2H
Reactions with Electron Deficient O
Alkenes HN N
Br
(-)-Manzacidin

M. P. Sibi, L. M. Stanley , T. Soeta, Org. Lett. 2007, 9, 1553.

Scheme 2

3.7.2 Reactions with Lithium Reagents

Organolithium reagents have been extensively used in enantioselective synthesis. In the
example shown below, the organolithium having the amine functionality binds with the
aldehyde which then undergoes attack by n-BuLi enantioselectively (Scheme 3).

OMe
Me

O n-BuLi, Ph N Ph OH
Li
Ph H Ph n-Bu
Et2O, CH2(OMe)2 (1:1)
-120 °C 90% ee

Scheme 3

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Chiral lithium enolate derived from LDA and optically active amide undergoes (3,3)-aza-
Claisen rearrangement to afford an intermediate for the synthesis of (-)-
verrucarinolactone (Scheme 4).

Me Me
N Ph N Ph Me O Me
LDA [3,3]
Me O toluene Me OLi N Ph
OH o 120 oC H
-78 C, 0.5 h OLi OH
66%

Aza-Claisen Rearrangement

O
HO
O

Me

Scheme 4

3.7.3 Reactions with Zinc Reagents

Organozinc reagents react with the aldehydes in the presence of a chiral ligand to form
the corresponding alcohol enantioselectively. In this case, first the organozinc reagent
reacts with the chiral ligand to form a chiral alkylating species that reacts with aldehydes
(Scheme 5).

AcO 4 Zn OBn OH
OBn O

Et H NHSO2CF3 Et OAc

NHSO2CF3 82% de
(0.08 equiv)

Scheme 5

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On similar lines the enantioselective addition of a Reformatsky reagent to an aldehyde or

ketone in the presence of N,N-diallylnorephedrine or (1S,2R)-N,N-di-n-butylnorephedrine
has also been achieved to afford corresponding β-hydroxyesters with up to 70% ee
(Scheme 6).

Me
N
Ph
O Me OH R Me
O Me O Me
+ BrZn Me
R Me
O Me OH O Me
73-75% ee

Scheme 6

Enantioselective cyclopropanation of cis and trans-allylic alcohols can be achieved by

using a chiral ligand under Simmons-Smith reaction conditions (Scheme 7). In this case,
the hydroxyl group on the substrate is necessary to coordinate with Zn.

NHSO2Me

NHSO2Me
(0.1 equiv)
Et2Zn (1.2 equiv)
ZnI2 ( 0.1 equiv)
Zn(CH2I)2 (1.0 equiv)
Ph OH Ph OH
CH2Cl2, 0 °C
80% ee

Scheme 7

Several studies have focused on the use of chiral Zn(II)-complexes for cycloaddition
reactions. The complex derived from Et2Zn and (R,R)-diisopropyltartrate can be used for
the cycloaddition of hydroxylimine with allylic alcohols to afford dihydroisoxazole in
96% ee (Scheme 8).

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Cl N O
OH PriO2C CO2iPr
OH OH
N
MeO HO OH
96% ee L
MeO
ZnEt2/L*

Scheme 8

Chiral Zn(II)-complex derived from (R,R)-BINOL and Schiff base derived from (R,R)-
cyclohexane-1,2-diamine can be used for hetero Diels-Alder reaction of aryl aldehydes
with 1,3-diene to give 2,3-dihydropyra-4-one derivative with excellent enantioselectivity
(Scheme 9).

Ar

OMe O N

O O Zn
10 mol% ZnL* O
+
O Ph N
TMSO Ph H CF3CO2H
98% ee, 99% yield Ar
ZnL*

Scheme 9

The industrial process for the transformation of (R)-citronellal to (-)-isopulegol uses

ZnBr2, which takes place via ene reaction (Scheme 10-11).

Me Me
Me
CHO
ZnBr2
OH +
O ZnBr2-
Me Me Me H
(-)-Isopulegol Me
(R)-Citronellal

Scheme 10

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Me

H Me H Me
O ZnBr OH =
2
H OH
Me
Me H H Me CH2
(-)-Isopulegol
Scheme 11

Polymer based catalysts have also been developed for the addition of Et2Zn to aldehydes
with good to excellent enantioselectivity. For example, chiral 1,2-diamine based polymer
has been used with Et2Zn as recyclable catalyst for the Et2Zn addition to aldehydes
(Scheme 12-13).

Ph Ph

1 mol % Poly-Zn OH
N N OC8H17
CHO Zn
2 equiv Et2Zn (S) O O
n
Toluene
NO2 30 °C, 18 h NO2 t-Bu t-Bu H17C8O
70% ee Poly-Zn
Scheme 12

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Mechanism

Ph Ph

N N OC8H17
Zn
O O
n

R'OZnEt t-Bu t-Bu H17C8O

O Et2Zn, ArCHO
OR' =
Ar Et Ph Ph Et2Zn, ArCHO

OC8H17 N N H
Zn Ar
O OR'O Ph O Ph
n
H17C8O t-Bu Zn t-Bu N N OC8H17
Et Zn
O Et O n

t-Bu Zn t-Bu H17C8O

Et

Scheme 13

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Problems

O O
N N

1. N Me
Zn, Br

Ph Ph NaH, Me3SO4
2.
OH OH

PPh2
O N

Me2N O
3.
1.2 equiv BuMgCl, 8 mol% CuI

OZnCl
Me
OTBS O

4. N
NO2

N
Li N

5. O
N

NHSO2C6H4-p-NO2

NHSO2C6H6-p-NO2
6. Ph OH
Et2Zn, CH2I2

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Text Book
M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004

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