Transition Metal Catalyzed Coupling Reactions

• Catalytic nucleophilic substitution reactions comprise some of the most commonly used
catalytic processes in synthetic organic chemistry.

• The original cross-coupling reactions formed C-C bonds, however catalytic carbon
heteroatom C-X formation has now been developed where X = N, O, S, P, Si, B.
• A list of well known (not comprehensive) C-C and C-X bond forming reactions is given below

Ulmann coupling & condensation
Mozoriki-Heck

Kumada
Stille

Negishi
Suzuki-Miyaura

Fukuyama
Sonogashira

Glaser & Hay
Buchwald-Hartwig

Hiyama-Denmark
Chan-Lam
 Cross-Coupling Reactions
• The mechanism of the various cross-
coupling reactions (with the exception
of the Heck reaction) includes three
stages:
1. Oxidative addition
2. Transmetalation (+isomerization)
3. Reductive elimination
• As we have already covered, oxidative
addition and reductive elimination are
multi-step as they involve ligand
association and dissociation
respectively.
• Transmetalation involves the exchange
of ligands between two metal centers.
 Homo-Coupling Reactions
• Homocoupling is less well studied
and thus understood as its cross-
coupling analogue.
• Suggested mechanism have
invoked sequential oxidative
addition of a aryl halide to produce
the LnMIVAr2Cl2 species.
Alternatively, once could image
how disproportionation of the L
LnMIIArCl species could lead to
LnMIIAr2. In each case reductive
elimination resulting in the
symmetrical bisaryl.
• Kochi showed using a
stoichiometric reaction involving a
Ni reagent that a more complex
mechanism is likely taking place
involving NiI , NiII and NiIII.
 Kumada Coupling
• In 1972 Kumada and Corriu independently reported he first Pd or Ni-catalyzed cross coupling
reaction towards C-C bond formation.
• Kumada coupling involves coupling of a Grignard reagent with alkyl, vinyl or aryl halides in
the presence of a Ni transition metal catalyst providing an economic transformation.
• Less efficient catalysts were reported earlier by Kochi (Fe) and Kharasch (Co & Cr).

• The reaction is limited to however to halide partners that do not react with
organomagnesium compounds. One example is in the industrial-scale production of styrene
derivatives, and the Kumada Coupling is the method of choice for the low-cost synthesis of
unsymmetrical biaryls.
• The advantage of this reaction is the direct coupling of Grignard reagents, which avoids
additional reaction steps such as the conversion of Grignard reagents to zinc compounds for
the starting materials in the Negishi Coupling.
 Negishi Coupling
• Since the reports of Kumada and Corriu, many advances have been made in the types of carbon
nucleophiles available for cross-coupling processes as alternatives to Grignards reagents.
• Although Grignard reagents are easy to generate, and many are commercially available, they
have low functional group tolerance.
• In 1977 Negishi reported the preparation of unsymmetrical biaryls in good yields via nickel- or
palladium-catalyzed coupling of organozinc compounds with various halides (aryl, vinyl,
benzyl, or allyl).

• The Negishi reaction has broad scope, and is not restricted to the formation of biaryls.
• Pd catalysts tends to be less sensitive to oxygen and are believed to be less toxic than their Ni
counterparts. Furthermore they tend to react without the intervention of radical intermediates
that can lead to side products (e.g. homocoupling, racemization, isomerization).
 L

Pd
L
L L

dba -dba

L I
Fe
reductive L Pd
elimination
oxidative
addition

L L
L Pd I Pd
L

Fe Fe
Cl Zn
L
isomer ization Pd tr ansmetalation
Fe L

I ZnCl
 Stille Coupling
• The Stille Coupling is a versatile C-C bond forming reaction between stannanes and halides
or pseudohalides, with very few limitations on the R-groups.

• The main drawback is the toxicity of the tin compounds used, and their low polarity, which
makes them poorly soluble in water.
• Stannanes are stable, but boronic acids and their derivatives undergo much the same
chemistry in what is known as the Suzuki Coupling.
• Improvements in the Suzuki Coupling may soon lead to the same versatility without the
safety drawbacks of using tin compounds.
 Miyaura Borylation

• The coupling of organoboron reagents has become the most commonly used cross-coupling
process. Organoboron reagents are less toxic than organotin reagents and tend to undergo
coupling reactions in the presence of a variety of functional groups.
• The Miyaura borylation reaction enables the synthesis of boronates by cross-coupling of
bis(pinacolato)diboron with aryl halides and vinyl halides.

• Borylated products derived from bis(pinacolato)diboron allow normal work up including

chromatographic purification and are stable towards air. Pinacol esters are difficult to
hydrolyze, but they may serve as coupling partners in the Suzuki Coupling and similar
reactions without prior hydrolysis.
• Crucial for the success of the borylation reaction is the choice of an appropriate base e.g.
KOAc, as strong activation of the product enables the competing Suzuki Coupling.
 PPh3

Pd
PPh3
Ph3P PPh3

2PPh3 -2PPh3

Ar'
isomer ization & PPh3
I
r eductive
elimination Ph3P Pd
oxidative
addition
PPh3
Ph3P Pd PPh3
O B I Pd
Ph3P
O
KOAc

PPh3
O PPh3
AcO Pd
B Pd KI
Ph3P
O Ph3P

O O O
AcO B B B
O O O

tr ansmetalation
 Suzuki Coupling
• The coupling of organoboron reagents has become the most commonly used cross-coupling
process. Organoboron reagents are less toxic than organotin reagents and tend to undergo
coupling reactions in the presence of a variety of functional groups.
• Like neutral organosilicon groups (Denmark rxn), however, neutral organoboron reagents do
not undergo metal-catalyzed cross-couping without an additive.
• Suzuki showed that addition of a hard base, e.g. OH− or F− , causes the organoboron reagent
to undergo cross-coupling by generating a four-coordinate anionic organoboron reagent that
transfers the organic group from boron to the metal catalyst.
• The scheme below shows the first published Suzuki Coupling, which is the palladium-
catalysed cross coupling between organoboronic acid and halides.
• Recent catalyst and methods developments have broadened the possible applications
enormously, so that the scope of the reaction partners is not restricted to aryls, but includes
alkyls, alkenyls and alkynyls.
• Potassium trifluoroborates and organoboranes or boronate esters may be used in place of
boronic acids. Some pseudohalides (for example triflates) may also be used as coupling
partners.
• One difference between the Suzuki mechanism and that of the Stille Coupling is that the
boronic acid must be activated, for example with base.
• This activation of the boron atom enhances the polarization of the organic ligand, and
facilitates transmetalation.
• If starting materials are substituted with base labile groups (for example esters), powdered
KF effects this activation while leaving base labile groups unaffected.
 PPh3

Pd
PPh3
Ph3P PPh3

2PPh3 -2PPh3

Ar' PPh3 I

Ph3P Pd
isomerization & oxidative
r eductive addition
elimination

PPh3 PPh3
'
Ar Pd I Pd
Ph3P Ph3P
K+ OAc
transmetalation KOAc
B O PPh3
AcO
O AcO Pd
Ph3P

OAc KI
O KOAc
+
Ar' B B O K
'
O Ar
O
 Sonogashira Coupling
• Compounds containing reactive C-H bonds have been shown to undergo cross coupling in the
presence of catalyst and base without initial formation and isolation of a main group derivative.
• One classic version of this coupling is the reaction of an aryl halide with a terminal alkyne to
form an alkynylarene.
• Although Heck and Cassar independently reported this reaction in 1975 Sonogashira reported
that reactions with added copper occur under milder conditions.

• The copper additive is believed to generate a copper acetylide which then reacts with the Pd
catalyst during the coupling process.
• This coupling of terminal alkynes with aryl or vinyl halides is now known as the Sonogashira
reaction and is performed with a palladium catalyst, a copper(I) co-catalyst, and an amine base.
• Typically, the reaction requires anhydrous and anaerobic conditions, but newer procedures have
been developed where these restrictions are not important.
 PPh3

Pd
PPh3
Ph3P PPh3

2PPh3 -2PPh3

reductive
elimination PPh3 I
R
Ph3P Pd
oxidative
addition

PPh3 PPh3
Ph3P Pd I Pd
Ph3P

R transmetalation
Cu R
PPh3
isomer ization R Pd
HNEt3 I
Ph3P
CuI

NEt3 + H R
 Mizoroki-Heck Coupling
• The Mizoroki-Heck C-C bond forming reaction is coupling of an aryl halide with an olefin to
cleave the C-H bond of the olefin and replace it with an aryl group.
• This reaction was first reported by Mizoroki but later developed and optimized by Heck.
• The reaction is most commonly conducted with electron-deficient olefins, such as styrene or
acrylate derivatives – the electronic properties of which tend to favor formation of conjugated
products.

• Recent developments in the catalysts and reaction conditions have resulted in a much broader
range of donors and acceptors being amenable to the Heck Reaction.
• Reaction with aliphatic electrophiles remains rare.
• One of the benefits of the Heck Reaction is its outstanding trans selectivity.
• The Mizoroki-Heck reaction follows a different course from the other cross-coupling ractions
after the oxidative addition step.
• The olefin coordinates to the metal center, e.g. PdII , after oxidative addition of the aryl or vinyl
halide.
• This ligand association may occur by associative displacement of amonodentate ligand from
the metal center or it may occur by replacement of haldie by the olefin to generate a cationic
olefin complex.
• In some cases the aryl or vinyl triflate may be used in place of the halide. In this case the olefin
readily displaces the triflate to generate a cationic metal-olefin complex.
• 1,2-insertion then takes place to generate a metal-alkyl intermediate. It is this 1,2-insertion
step that controls the regioselectivity of the Mizoroki-Heck reaction.
• Subsequently, β-elimination occurs to generate the metal-hydrido-alkenyl product.
• Following dissociation of the product, nucleophilic abstraction by a base removes a proton
regeneration the fully reduced metal catalyst.
 PPh3

Pd
PPh3
Ph3P PPh3

2PPh3 -2PPh3

HNEt3Br
reductive PPh3 Br
elimination
Ph3P Pd
oxidative
NEt3 addition

PPh3
H Pd Br PPh3
Ph3P Br Pd
O O
Ph3P

dissociation O
O association

O
O
O
O

PPh3 Br Pd
H Pd Br
Ph3P Ph3P PPh3

O PPh3
elimination O 1,2-insertion
Pd Br

H Ph3P
 Buchwald-Hartwig Coupling

• Palladium-catalyzed synthesis of aryl amines. Starting materials are aryl halides or

pseudohalides (for example triflates) and primary or secondary amines.
• The synthesis of aryl ethers and especially diaryl ethers has recently received
much attention as an alternative to the Ullmann Ether Synthesis.
• Newer catalysts and methods offer a broad spectrum of interesting conversions