This document discusses various carbon-carbon coupling reactions, including transmetallation, Suzuki coupling, Stille coupling, and their mechanisms and applications. It provides details on: 1. Transmetallation is an organometallic reaction that transfers ligands between metals, activating a metal-carbon bond and forming a new one. It can be used in cross-coupling reactions to form C-C bonds. 2. Suzuki coupling is a cross-coupling reaction between an organoboron compound and halide catalyzed by palladium. It is widely used in pharmaceutical synthesis. 3. Stille coupling reacts an organotin compound with an organic halide catalyzed by palladium and can

1. CARBON-CARBON
COUPLING REACTIONS
MC-730
PRESENTED BY:
Kotwal Bilal
MC/Ph.D./2022/01
NIPER-HYDERABAD

2. ORGANOMETALLIC
CHEMISTRY
 The term Organometallic was introduced by E. C. Frankland. He was working on arsenic
compound and first synthesized organomercury compound in 1848
 A compound which contain at least one metal carbon bond for e.g. Li(CH3)4, Al(CH3)6
 But the electronegativity of metals are less than carbon
 Most of the metals are of main group elements or transition metals or lanthanides and
actinides are bonded to carbon containing ligands such as alkyl, alkene, aryl groups
 Transmetallation is a type of organometallic reaction that involves the transfer of ligands (i.e.,
alkyl, aryl, alkynyl, allyl, etc.) from one metal to another, activates a metal-carbon bond and
forms a new metal-carbon bond. It has general form:
 Transmetallation is an equilibrium process the transfer of organic ligands to more
electropositive metals
 In this process, the metal-carbon bond is activated, leading to formation of new metal-carbon
bonds.
TRANSMETALLATION

3.  The reaction is usually an irreversible process due to thermodynamic and kinetic reasons
 Thermodynamics reaction based on the EN of the metals and kinetics reaction if there
are empty orbitals on both metals
 There two types of Transmetallation reactions
 1. Redox-transmetallation: a ligand is transferred from one metal to the other through
an intermolecular mechanism.One of the metal centre is oxidized and the other is
reduced. EN is the driving force for the reaction to go forward.
2. Redox-transmetallation/ligand-exchange: The ligands of two metal complexes
switch places with each other. It proceeds in a concerted manner.
Applications: 1. Cross coupling reactions: Used in the catalytic cycles of cross-
coupling reactions. For e.g. Stille cross-coupling, Suzuki cross-coupling, Sonogashira
cross-coupling, and Negishi cross-coupling. General form is; R′–X + M–R → R′–R + M–X
and are used to form C–C bonds
2. Lanthanides: Lanthanide organometallic complexes have been synthesized by RT
and RTLE

4.  A coupling reaction in organic chemistry is a general term for a variety of reactions
where two fragments are joined together with the aid of a metal catalyst
 Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki were awarded the 2010 Nobel Prize in
Chemistry for developing palladium-catalyzed cross coupling reactions
 In one important reaction type, a main group organometallic compound of the type R-M
(R = organic fragment, M = main group center) reacts with an organic halide of the type
R'-X with formation of a new carbon-carbon bond in the product R-R'
 Cross coupling reactions divided into two main parts
 1. Homocoupling Reactions
 in this type of reaction involve two similar molecule coupling together to form new
molecule for example Ullman Reaction
 e.g. Wurtz reaction, Glaser coupling, Pinacol coupling reaction
COUPLING
REACTIONS

5.  2. Cross Coupling reactions
 In this type of reaction involve two different molecule coupling together to form new
molecule an illustrative cross-coupling reaction is the Heck coupling of an alkene and an
aryl halide:
 In C-C cross coupling reactions C-C bond formation between organic electrophile (RX)
and nucleophile (R1M) in presence of transition metal catalyst, usually Pd ( even Cu, Ni,
Fe also used.)
 These are the main reactions which are related to the C-C cross coupling reactions
Reaction Reactant 1 Reactant 2 Catalyst
Kumada R-MgX RX Pd or Ni
Heck Alkene RX Pd
Sonogashira Alkyne RX Pd or Cu
Nigishi R-Zn-X RX Pd or Ni
Stille R-Sn-R3 RX Pd
Suzuki R-B-(OR)2 RX Pd
Hyiama R-Si-R3 RX Pd

6. Why Palladium???
• Palladium is d-block transition metal
• Pd favours the formation of tetrahedral d10 and square planar d8 complexes of low
oxidation states ( 0 and II respectively)
• This features affords Pd good electron donating and electron accepting capabilities,
allowing fine-tunig by altering the electronic properties of its ligands
• Pd may easily participate in concerted process due to its closely lying HOMO and LUMO
energies
• Pd complexes tends to be less sensitive to oxygen and are less toxic

7. MECHANISM OF C-C CROSS COUPLING REACTIONS
1. Oxidative Addition
• Oxidative addition of organic electrophiles to Pd(o) is the 1st step
• Increases both oxidation state and coordination number
• Oxidative additions may proceed via two major pathways
a) Concerted Mechanism: found in nonpolar reagents and aryl halides. Retention of
configuration is in case of chiral A-B reagents
b) SN2 Mechanism: its associated with the bimolecular process. Often found in addition of
polar reagents and in polar solvents. Result in inversion of configuration

8. 2. Reductive Elimination
• It is the reverse of oxidative addition
• It involves the elimination or expulsion of a molecule from a transition metal complex. In
the process of this elimination, the metal centre is reduced by two
3. Migratory Syn-Insertion (Carbopalladation)
• Involve the addition of a C-M bond of an organometallic across C-C multiple bond lead to
form new organometallic as in following reaction followed by syn-insertion
• This process is sensitive not only to steric but also electronic factors, which in turn
influences the regiochemical outcome of the reaction

9. 4. Beta-Hydride Elimination
• can either be a vital step in a reaction or an unproductive side reaction
• β-hydride elimination may occur if a β-hydrogen is accessible

10. SUZUKI-MIYAURA COUPLING
• Suzuki-miyaura coupling is a metal catalyzed reaction, typically with Pd, between an
oranoborane (boronic acid or boronic ester or aryl trifluroborane) species and halides or
triflates under basic conditions.
• It creates C-C bonds to produce conjugated systems of alkenes, styrenes or biaryl
compounds.
• First suzuki-type cross coupling reaction between phenylboronic acid and haloarenes was
published by Akira Suzuki and N. Miyaura in 1981.

11. REACTION MECHANISM
• Oxidative addition:
 Rate determining step
 Reactivity order : I> OTf> Br> Cl
 Oxidative addition proceeds with retention of stereochemistry
with vinyl halides, while giving inversion of stereochemistry with
allylic and benzylic halides.
• Transmetallation:
 Base encourages the transfer of alkyl group from organoborane
to Pd complex
• Reductive elimination:
 Cis complex is needed (trans isomerizes to cis to undergo
reductive elimination).
 First order kinetics (rate and reaction is dependent only on
concentration of post-transmetallation Pd-complex).
 Order of reductive elimination: Ar-Ar > Ar-R > R-R.

12. CATALYSTS
• Palladium catalysts are most widely employed in Suzuki coupling. The active Pd catalyst
consist of two parts: precursors and ligands.
• To enhance the reactivity and stability of the catalyst, they were developed to be electron-
rich and spatially bulky, which affords a high turnover number (TON) and low loading.
• For example, palladacycles were developed and exhibit thermal stability, robust reaction
times, insensitivity to air and water, low cost, and environmentally friendly
• Polymer-supported heterogenous catalysts were developed for preventing contamination
of ligand residues with products, fast recovery of catalyst, easy separation and recycling
in pharmacuetical and industrial synthesis.

13. LIGANDS
• Ligands are to be electron-rich (facilitates the oxidative addition) and spatially bulky
structures (enables reductive elimination)
• Phosphine ligands: PPh3 was the earliest and most widely used monodentate
phosphine ligand in Suzuki reactions. Substitutions on the phosphor atom and aromatic
ring gave high catalytic reactivity on less reactive substrate
• Buchwald group has synthesized a series of dialkylbiaryl ligands

14. ORGANOBORANES
• Boronic acids are highly reactive towards transmetallation and are atom efficient. Boronic
esters are less reactive than boronic acids. Loss of hydrogen bonding makes them less
polar and easier to handle.
• Acyclic boronic esters are readily hydrolyzed, while cyclic are more robust and are stable
to aqueous work-up
 Synthesis of organoborane reagents
• React Grignard reagents with borate esters, followed by hydrolysis.
• React arylsilanes with boron tribromide, followed by acid hydrolysis.

15. Catalysts Boranes
Eg: Pd*, Ni, Ru, Fe, Cu Eg: Boronic acids, esters and tri-fluoro
derivatives
Palladium catalysts: most widely used with
electron-donating (phosphine) ligands
EWD groups increases the reactivity of the
borane. ArBF3 > RB(OH)2 > RB(OR)2 >> R3B
Nickel catalysts: reactive with inert
electrophiles, like chlorides, aryl fluorides,
carbamates, phosphate esters and
unreactive bromides
Alkyl boranes are the least reactive in
transmetallation. needs the use of stronger
bases
Nickel’s variation in oxidation states (Ni0 to
Ni2+ and Ni+ to Ni3+) and increased
nucleophilicity due to its small size
Selecting a borane for a reaction depends on
its compatibility with its electrophile coupling
and desired borane R group

16. REGIO AND STEREOSELECTIVITY
• Oxidative addition of alkyl and alkenyl halides retains the configuration of the electrophilic
substrate.
• Transmetallation and reductive elimination both retains the regio- and stereochemistry
established in oxidative addition.
• Chiral centers are formed by using chiral borane reagents. These reagents perform
asymmetric cross coupling with retention of configuration i.e. (R) boranes yield (R)
products
• Borane Substrates: Easy to synthesize, stable, nontoxic, cost effective and minimal health
risks. Organoboranes are nontoxic and stable to extreme heating and exposure to oxygen
or water.
• Reaction Conditions: Milder and Greener.
• Boranes are exceptionally nucleophilic, and thus do not require extreme conditions for
transmetallation.
• Suzuki couplings can be performed in heterogeneous or purely aqueous conditions.
• The by products are typically salts and water soluble, i.e. the reaction has a high atom
economy.
ADVANTAGES OF SUZUKI COUPLING

17. LIMITATIONS
•Synthesis of complicated borane substrates in lab is often difficult
• Some alkyl borates (sp3) and hetero- substrates don’t show reactivity
• Chloride substrates react slowly, and with lower yields
• Without the use of base it leads to many side products
•Side reactions: β-hydride elimination competes with reductive elimination, mostly
observed with reactants that have β-hydrides leading to low yield. Can be avoided by
using Ni catalysts or ligands with larger bite angles

18. SYNTHETIC APPLICATIONS
• Industrial synthesis: Suzuki cross coupling reaction to synthesize the FDA approved anti-cancer
drug Linifanib (tyrosine kinase inhibitor).
• Natural products synthesis: Suzuki coupling is applied in the total synthesis of anticancer drug
Epothilone A.
• Suzuki-Miyaura coupling reaction for the synthesis of (-)steganone
Kruger, et al., Org. Process. Res. Dev. 2009, 13, 1419-1425
Meng, D., J. Am. Chem. Soc. 1997, 119, 10073-10092
Yalcouye, B., Eur. J. Org. Chem. 2014, 28, 6285-6294.

19. STILLE COUPLING
• The Stille reaction, named after the late John Kenneth Stille, is a Pd-catalyzed cross
coupling reaction of an organic halide with an organotin compound.
• The foundations were laid by Eaborn and Migita in the late 70’s. Eaborn’s process
involved formation of diary product using an organotin reagent. Migita coupled acyl
chlorides with organotin reagents to form ketones with yields ranging from 53-87%.
• In 1978, Stille published a report on the coupling of alkyl tin reagents with acyl and aryl
halides under milder conditions with higher yields (76-99%).

20. REACTION MECHANISM
• Oxidative addition: electrophile binds to Pd(0) in a concerted fashion, turning it into a 16-
electron Pd(II) cis square planar intermediate.
• Transmetallation: organostannane reagents introduces the R1 group and also takes
away the halide.
• Reductive elimination: Finally, the two R groups will be coupled and the catalyst comes
back to the 14-electron Pd (0) state.

21. • Ligands: Pd(0) catalyst: Pd(PPh3)4 and Pd(dba)2
Pd(II) complexes: Pd(OAc)2, PdCl2(MeCN)2, PdCl2(PPh3)2
• Organostannanes: Alkynyl > Alkenyl > Aryl > Allyl = Benzyl > α-alkoxyl > Alkyl
• Electrophiles: Vinyl, aryl and heterocyclic halides can be used as the electrophile for the
reaction. Chlorides are too inert for oxidative addition and iodides react faster than
bromide.
• In some cases, LiCl, Cu(I) and Mn(II) salts are used to increase reaction rate and
selectivity in case of bulky organotin reagents.
• Polar solvents such as NMP, DMF and DMSO at reflux temperature are preferred.
Advantages
 Organotin reagents are air stable, commercially available or readily synthesized and have
great versatility of functional group tolerance.
 It can be used to synthesize a wide range of compounds including styrenes, aromatic
ketones and biaryl derivatives

22.  A wide variety of aryl, vinyl and acyl halides or pseudo halides can be used as
electrophiles. Heterocyclic halides can also be used.
 Aryl, alkyl, vinyl and even heterocyclic stannanes can be used.
 Stereochemistry is typically retained in Stille coupling.
 Limitations
• Organotin reagents are highly toxic, costly.
• The most commonly employed catalyst in the Stille reaction i.e.,
tetrakis(triphenylphosphine) palladium(0) [Pd(PPh3)4] is instabe, as it is oxidized by traces
of oxygen to its oxide, Ph3PO.
• Under conditions for either stille or suzuki coupling to ensure, primarily suzuki occurs
• Organic chlorides are not reactive enough to undergo oxidative addition with the Pd
catalyst.
• Bulky or heavily substituted reagents tend to react very slowly and may require
optimization, typically in the form of co-catalytic copper iodide.

23. APPLICATIONS
• Total synthesis of the marine alkaloid Ircinal A (antitumor substance)
• Ailanthoidol is synthesized by using 5-bromo-2-hydroxy-3-methoxy benzaldehyde.
• Synthesis of Doravirine : Non-nucleoside reverse transcriptase inhibitor developed by
Merck & Co. for use in the treatment of HIV/AIDS
• Synthesis of steroids: Stille cross-coupling of enantiomerically pure cycloalkenyl
stannane and enol triflate
Stepehen, F ., J. Am. Chem. Soc.1999,121, 866-867
Lin, S. Y., J. Org. Chem. 2003, 68, 2968-2971
DOI: 10.1021/acs.orglett.7b01142
Org. Lett. 2017, 19, 3071−3074
Sunnemann, et al., Org. lett, 2007 , 9, 517-520.

24. • SYNTHESIS OF AUREOTHIN
• ROLE OF COPPER SALT IN COUPLING REACTIONS:
• Polymerization reaction(microwave assisted)
Lee, V., 2019. Organic & biomolecular
chemistry, 17(41), pp.9095-9123.
Baldwin, J. E.; Mee, S. P.H.; Lee,
V. Chem. Eur. J. 2005, 11, 3294–
3308
Raj, M.R et.al,2017. Journal of
Materials Chemistry A, 5(7), pp.3330-
3335.

25. HIYAMA COUPLING
• Hiyama couplings were first reported by Yasuo Hatanaka and Tamejiro Hiyama in 1988
• It is a palladium catalyzed cross coupling reaction of organosilanes with organic halides
or triflates promoted by the activation of the organosilane with fluorides.
• In 1978, Kumada reported the organo(pentafluoro)silicates cross-coupling with allylic
electrophiles through transmetalation of pentafluoro silicates with Pd(II)
• Hiyama and Hatanaka developed a protocol to generate hypervalent silicate species in
situ from readily available tetracoordinate organosilanes.

26. MECHANISM
• Oxidative addition of organic halides with
Pd(0) occurs and forms Pd(II) species.
• Pentacoordinate silicates are generated in
situ.
• Fluorine enhances the Lewis acidity of the
silicon centre for the formation and stability
of pentacoordinate silicates.
RECENT
ADVANCEMENT
• Hiyama cross-coupling reactions between aryl siloxanes and cyclic racemic allyl halides
by Rh(I)-catalyzed system.
Jesús, G.,
organomettalics, 2019

27. • Trimethylvinylsilanes can be used to directly vinylate aryl and vinyl iodides
• Triethoxysilyl group is more effective in the cross-coupling with aryl iodobenzene than the
phenyldimethylsilyl or trimethylsilyl derivatives.
• Dimethyl silanols and their salts can provide desired product under mild conditions in high
yield.
• Synthesis of 1-benzoxocane: Synthesis of trisubstituted Z-styrenes by Hiyama-type
coupling of oxasilacycloalkenes and aryl iodides
• Hiyama coupling of aryl siloxanes with aryl bromides catalyzed by a Pd NanoParticles in
water
• Water and acid additive effect in palladium-catalyzed Hiyama coupling of ArCl by a
Beilstein , J. Org. Chem. 2017, 13, 2122–2127.
Aazam . M., RSC Adv., 2019, 9, 3185–3202
On. Y., Chem. Eur. J. 2016, 22, 6471 – 6476

28. HIYAMA–DENMARK COUPLING
o In 2008, Denmark reported the fluoride free activation
of organosilanes
o By use of Bronsted base, like organosilanol and their
salts
o Fluoride is not needed as activator, so the reaction is
compatible with substrates bearing silyl-protecting
groups and can be performed in large-scale reactors.
 Advantages
o Low environmental impact
o High atom efficiency
o Stability and availability of organo silanes
o Safe handling compared with the organoboron and organozinc compounds
 Drawbacks
o The Hiyama coupling is limited by the need for fluoride in order to activate the
organosilicon reagent.
o The fluoride ion is also a strong base, which can cleave any base sensitive silicon
protecting groups (e.g. silyl ether), acidic protons and functional groups which are
frequently employed in organic synthesis

29. DEVELOPMENTS IN HIYAMA COUPLING
• Hiyama coupling without fluoride activation: In 1997, Hatanaka and Hiyama reported the
fluoride free Hiyama coupling assisted by NaOH as better activater than the fluoride
• Phosphinous Acid-Catalyzed Cross-Coupling: Wolf and Lerebours reported the
Palladium−Phosphinous acid catalyzed NaOH promoted cross-coupling reactions of
Arylsiloxanes with aryl chlorides and bromides in water

30. NEGISHI COUPLING REACTION
• Introduced by Ei-ichi negishi, Anthony O King, Nobuhisa Okukado in 1977
• Proposed a general and selective procedure for synthesis of E,E and E,Z dienes using
(E)-alkyl alanes with alkenyl halides in presence of Pd or Ni
• Initially, reaction was done with alkenyl alanes and aryl halides
• Current reaction is used for cross coupling of aryl / benzyl zinc derivatives and alkyl/aryl
halides in presence of Pd or Ni
• Reaction and Mechanism
RZnX + ArX' R-Ar
Ni (PPh3)4 or Cl2Pd (PPh3)2
DIBAL-
H
Ar-R ArX
RZnX
ZnX2
Oxidative addition
Reductive elimination
Transmetalation
Pd0
Pd X
L
Ar
L
Pd
Ar
R
L
L

31. Different Catalysts used for Negishi Coupling
1. Palladium
o Air-moisture stable aminobiphenyl based palladacycle catalyst
o N-heterocyclic carbene based Pd complexes eg: Pd-PEPPSI –ipent-Cl
2. Nickel
• Standard catalysts with phosphine ligands : Ni (acac)2 + DPE-Phos
• Without phosphine ligands : Ni (COD)2 + TMEDA + 2-chlorotoluene
• Pincer ligands + Aryl trimethyl ammonium iodide
3. Others catalysts
• Cu, Fe, Co etc are used
• Fe + monophosphine ligands are excellent catalysts for alkyl/aryl/ allyl zinc
substrates
• Cobalt salts are also used , eg: CoBr + MeCN, CoCl .2LiCl +TMEDA

32. FACTORS AFFECTING NEGISHI COUPLING
1. Nature of organozinc reagent
• ZnRX undergoes transmetalation to form trans-product then isomerises to form cis
product, then finally reductive elimination
• Whereas ZnR2 forms cis product first then to trans
2. Presence of EWG/Lewis acid on catalyst
• Increases the rate of the reaction
3. Nature of solvent
• Rate increases if the dielectric constant of the solvent is more
4. Concentration of catalyst and oragnozinc substrate
• If Organozinc concentration is excess, results in decreased catalytic activity
L
Pd
L
L R
R
1
Zn
X
L
Pd
R
1
L R
R
1
Pd
L
L R
Trans Cis
R R
1
L
Pd
L
L R
R
1
Zn
R
2
L
Pd
R
1
L R
R
1
Pd
L
L R
Cis Trans
R R
1

33. DISADVANTAGES
 High cross/homocoupling ratios
 Does not require and isolation and
purification of any intermediates eg:
alkenyl halides
 Mild and fast procedure with high
chemoselectivity and regioselectivity
 Organozinc derivatives can tolerate
various electrophilic functional groups
eg; CN, COOCH3
 Preferred over conventional friedal crafts
method
ADVANTAGES
 Pd is toxic and expensive
 Pd can tolerate Nitro groups but reaction
rate is slower and quite the opposite for
Ni
 Most of the organozinc halides are
sensitive (Mg salts, Dioxane etc)
 Undesired β-hydride elimination

34. APPLICATIONS OF NEGISHI COUPLING
1. Synthesis of Canaglifozin (to treat type 2 diabetes)
• Canagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor
2. Synthesis of complex natural products eg: coelenterazine
3. Synthesis of Isodesmosine
N
N
Cl
O
C
H3
N
N
Cl
O
C
H3
O
1) TMP.MgCl,LiCl
2)ZnCL2,-
45 o
C, 1h
3)PhCOCl, PdPPH3
N
N
H
O
C
H3
N
OH

35. 4. For preparation of highly functionalised pesticides
5. Diastereoselective arylation eg: cyclohexane derivatives

36. Recent developments
1. Use of palladocycles
• Helpful in alkylating secondary alkyl zinc species
• By incorporating sterically hindered ligands can stabilise the zinc and leads to
lowered isomeric products
2. Use of N-Heterocyclic carbene complexes.
• Mostly preferred catalyst for coupling alkyl/heteroaryl zinc reagents
• Can tolerate various functional groups
3. Lithium chloride acceleration
• Accelarates the reaction by removing oxide impurities from metal surface
• Stabilises newly formed zinc complexes.
4. Use of Organosodium compounds

37. KUMADA COUPLING REACTION
 Was introduced in 1972 By M Kumada, Tamao K, Sumitani K and Corriu RJP ,
Commonly known as Kumada-Tamao-Corriu Coupling
 Coupling of Aryl/vinyl/alkyl halide with organomagnesium compounds (Grignard’s
reagent) in presence of catalysts such as Nickel and Palladium
 Due to toxicity of Palladium, Nickel is preferred as catalyst
 The first Kumada reaction was performed for the synthesis of trans-stilbene by coupling
β-bromostyrene and Phenyl Magnesium bromide
REACTION AND MECHANISM
Ni
R
1
X
L
L
Ni
R
L
L R
1
Ni R
L
R
1
L
Ni(0)
RMgX
MgX2
R
1
X
Oxidative
addition
Reductive
elimination
Trans/cis
Isomerization
Transmetalation
R1 -R

38. CATALYSTS
1. Nickel
• Generally used catalyst: Dichloro(1,3-
bis(diphenylphosphino)propane)nickel (Ni (dppe) Cl2)
• Nickel acetoacetonate
• Nickel N,N,N pincer systems
• Nickel with tridentate pincer bisaminoamide ligands eg: (HNN) Ni (2,4-
lutidine)Cl
2. Organoiron compounds
• eg: Dimesityl iron complex { Fe(II) Mes2-(SciOPP)}
• As precatalyst with chelating amine ligands eg: FeCl2 + TMEDA
3. Palladium- eg: Palladium diacetate , Palladium tetrakis triphenyl
phosphine {Pd(PPh3 )4}
4. Phosphonamide linked Cobalt/Hafnium complex
• Eg: ICo( IPr2PNMes)3 HfCl
5. Manganese
• Eg: MnCl2 More environment friendly than Ni/Pd

39. Factors affecting Kumada Coupling
1. Nature of Ligand
• Electron donor atom helps in the binding of Magnesium to the catalyst
• Stabilisation of metal atom is determined by the ligands
• Eg: Pincer ligands: Bis oxazolinyl phenyl amido ligand (Bopa)
• Ligands can prevent formation of β-elimination products
• Eg: N-heterocyclic carbene complexes
• Sterically hindered or bulky ligands reduces the β-hydride elimination side products
Eg: Pd(CH3CN)2Cl2 + 1,1'-Bis(diphenylphosphino)ferrocene
2. Nature of Grignard reagent
• Excess concentration of Grignard reagent retards the catalytic activity
• Presence of electron donating groups favours the reaction.
• Electron richness and steric properties determines the rate
• 3. Nature of alkyl halide
• Depending upon the type of catalyst used, different efficiency was observed.
• Grignard reagents show low reactivity towards haloarenes

40. Stereoselectivity
Both cis- and trans-olefin halides promote the overall retention of geometric configuration
when coupled with alkyl Grignards
Chemoselectivity
Grignard reagents do not typically couple with chlorinated arenes. This low reactivity is the
basis for chemoselectivity for nickel insertion into the C–Br bond of bromochlorobenzene
using a NiCl2-based catalyst
Advantages Disadvantages
• nickel makes reaction faster (small size)
• Less addition reaction compared to organozinc compounds
• Works at mild reactions conditions
• Functionalised groups
cannot be tolerated
such as ester , nitro
etc

41. APPLICATIONS OF KUMADA COUPLING
1. Synthesis of Aliskeren
2. Synthesis of Diflunisal

42. 3. Synthesis of photoresistors eg: p-tert-Butoxystyrene
3. Synthesis of polymers and synthetic reagent eg : p-chlorostyrene
 Recent developments in Kumada coupling
1. Ligand free catalysis
• Efficient construction of aryl substituted hydrocarbons with less amount of nickel
• Ligand free iron catalysis are also introduced
2. X Hetero dinuclear Co-Zr coupling
• promotes a low-energy electron-transfer alkyl halide oxidative addition mechanism.
• provide a dialkyl intermediate with a low-energy C–C bond forming reductive elimination
route through a phosphine dissociation pathway

43. 3. Use of Knochel-Hauser / Kumada-Corriu coupling for functionalised aromatic
heterocycles: K-H bases-TMP.MgCl.LiCl and TMP2.MgCl.2LiCl
4. Visible light Promoted Iron catalysed Kumada Coupling
N
N
N
O
Boc
TMPMgCl.LiCl, THF, 23 o
C, 1h
ZnCl2
SPhos, PhI
N
N
N
O
Boc

44. HECK REACTION
• It is a C-C coupling reaction between aryl halides or vinyl halides and alkenes in the presence
of a palladium-catalyst and base, which was named after American chemist Richard F. Heck.
• It is also known as Mizoroki-Heck reaction
• Awarded Nobel prize in year 2010
• Converts terminal alkenes into internal alkenes
• The analgesic naproxen is an example of a compound that is prepared industrially using the
Heck reaction
• General Reaction
• Catalyst:- Pd mostly; Sometimes Ni
• Solvents:- N,N-dimethylacetamide (DMA), DMF, dioxane, water, toluene, hexane, ethanol
• Bases:- Tertiary amines (NEt3, NBu3), alkali salts like carbonates, acetates or phosphates,
hydroxides and fluorides
• Ligands:- Phosphine, Carbene, NHC, BINAP

45. REACTION MECHANISM

46. HECK REACTION: REGIOSELECTIVITY OF MIGRATORY
INSERTION
• Migratory insertion of the olefin into the Pd-R bond can control the regio-selectivity of
Heck reactions.
• For a neutral palladium complex, the regioselectivity is governed by sterics, which means
nucleophilic attack happens on the less hindered site of the alkene
• For cationic palladium complexes, the regioselectivity is governed by electronics, which
implies that nucleophilic attack occurs on the site possessing the least electron density of
the alkene
Acc. Chem. Res. 1995 28, 2-7.

47. INTRA-MOLECULAR HECK REACTION
Tetrahedron, 1977, 12, 1037;
• A major issue in intramolecular Heck reactions is the mode of ring closure, i.e., exo
versus endo
HECK REACTION: MODIFICATIONS
1. Tandem Heck Reactions: When β-hydride elimination is not possible, additional
reaction pathways may unsue like carbonylation / alkylation
J. Org. Chem., 1993, 5304:
JACS, 1999, 5467

48. 2. Ionic liquid Heck reaction: In this variation, the reaction is executed in the presence of
an ionic liquid in order to avoid phosphorus ligands. This variation allows the reaction to
proceed in water and makes the catalyst reusable.
3. Heck oxy-arylation:- observes the displacement of the palladium substituent by a
hydroxyl group in the syn addition intermediate. This variation yields a product with a
dihydrofuran ring
Org. Lett., 2006, 8, 1237-1240
Arkivoc, 2009, 103-110

49. HECK REACTION: APPLICATIONS
• Naproxen:
• Taxol:
J. Org. Chem, 2000, 65, 7792
J. Am. Chem. Soc. 1996, 118, 2843.

50. HECK REACTION: ADVANCES
• Photo-irradiation Induced Heck Reaction of Unactivated Alkyl Halides at Room
Temperature
• Continuous-flow Mizoroki-Heck Reactions under Microwave Heating Conditions
J. Am. Chem. Soc., 2017, 139, 18307-18312
Angew. Chem. Int. Ed., 2006, 45, 2761–2766

51. Org. Lett. 2019, 21, 3, 776–779

52. SONOGASHIRA REACTION
• Discovered in 1975 by Kenkichi Sonogashira, Yasuo Tohda and Nobue Hagihara (Osaka
University in Japan)
• Couple a sp hybridized carbon from terminal Alkyne with a sp2 carbon of an Aryl/Vinyl
halide or triflate
• The reaction requires anhydrous and anaerobic conditions
• Employed in the synthesis of specific alkynes , conjugated enynes
• The reaction introduced the concept of utilizing copper iodide as a co-catalyst
(Alternatives zinc, tin, boron, aluminum and Ag2O)
• Sonogashira reaction remains one of the most popular cross-coupling reactions for the
formation of C(sp2)-C(sp) bond

53. Sonogashira reaction: Mechanism
• Sonogashira reaction: Order of reactivity
• Vinyl iodide > Vinyl triflate > Vinyl bromide > Vinyl chloride >aryl iodide >aryl triflate >aryl
bromide >aryl chloride
Tet. Lett. 1975, 16, 4467–4470

54. Limitations of Copper in the reaction
• Copper co-catalyst is added to increase reactivity, but the presence of copper can result in the
formation of alkyne dimers, which are undesired homo coupling products of acetylene derivatives
upon oxidation
• It is necessary to run the reaction in an inert atmosphere to avoid the unwanted dimerization.
• Copper-free variations to the Sonogashira reaction have been developed to avoid the formation
of the homocoupling products
• High loading of amines and also expensive method
• Regioselectivity in sonogashira reaction is seen in aryl or vinyl halides with two different
halide substititions.
• Reactivity order of aryl or vinyl halide towards oxidative addition: Vinyl iodide > vinyl triflate > vinyl
bromide > vinyl chloride > aryl iodide > aryl triflate >aryl bromide > aryl chloride
Tet. Lett. 2005, 46, 6697–6699

55. Copper-free Sonogashira reaction:
Org. Lett. 2003, 5, 4191.

56. Sonogashira reaction: Other Modifications
1. Nickel Catalysed Sonogashira reaction:
2. Gold Co-catalyst Sonogashira reaction:
3. Palladium free Iron Catalysed Sonogashira reaction:
4. Inverse Sonogashira reaction
J. Am. Chem. Soc. 2009,
131, 12078–12079
Synthesis 2013,
45, 817–829
Angew. Chem. Int. Ed. 2008,
120, 4940-4943
Angew. Chem. Int. Ed. 2010,
49, 2096 –2098

57. SONOGASHIRA REACTION: APPLICATIONS
1. Natural Products:
2. Pharmaceuticals: It has shown potential in the treatment of Parkinson’s disease,
Alzheimer’s disease, Schizophrenia
3. Alkynylation of phenyl alanine:
Eur. J. Org.
Chem. 2005 (13): 2689–
2693
Top. Organomet. Chem.,
2004, 6, 205–245
Org. Lett. 2006, 8, 9,
1883–1886

58. 4. Synthesis of the Strychnine:
5. Synthesis of the Filibuvir:
Org. Lett. 2000, 2,
2479.
Org. Process Res. Dev.
2014, 18, 26−35