MKG LECTURE 11

06/04/2023
 Suzuki- Miyaura Reaction

Suzuki coupling can be described as a Pd catalysed cross-coupling reaction of

organoboron compounds (boronic acid or ester) with organic halide.

BR2 = B(OH)2, B(OR’’)2, 9-BBN, B(CHCH3CH(CH3)2,

X = I, Br, OSO2(CnF2n+1) and Cl (with bulky electron-rich phosphine),
R = aryl, alkenyl and alkyl,
R’ = aryl, alkenyl, alkenyl, benzyl, allyl,
[Pd] = Pd(PPh3)4, Pdcl2(R3P)2, pd(OAc)2, Pd2(dba)3, PdCl2(dppf),
Base = Na2CO3, NaOEt, NEt3, K3PO4 or CsF
Solvents = Benzene, THF, DMF etc
It required mild reaction condition then heck Reaction.
It is the most useful reaction in industries for C-C bond formation .
Examples

BY2 = B(Sia)2, B(OiPr)2

Mechanism

Oxidative addition Reductive

Elimination

Transmetallation
 Industrial Application

• Synthesis of vicenistatin (antitumor and antibiotic)

Synthesis of Rutamycins (antifungal)
 Sonagashira Coupling Reaction

This coupling of terminal alkyne with aryl or vinyl

halide is performed with pd catalyst, Cu as cocatalyst
and amine as base.

Advantage: The geometry of the starting compound

is preserved in the Sonagashira coupling reaction.
Mechanism
Examples
 Industrial applications
• It is the most widely used coupling reaction in the pharmaceutical
industry and in the case of organic material chemistry.
• Sonogashira coupling is used to construct the core skeleton of
dynemicin A and calicheamicin γ1 a potent enediyne containing
antibiotics.
 Stille Coupling Reaction

• Palladium catalysed cross coupling reactions involving

organotin based reagent and organohalide are referred to
as still coupling reaction.

X = Br, I, OSO2CF3, OAc, Cl (When L = PBut3 )

R1 = Acyl, alkenyl, aryl, ally, benzyl
R2 = alkynyl, alkenyl, aryl, allyl, benzyl, acetonyl
R3 = Me, n-Bu
 Advantage:
• No activation of organostannyl reagent is required.
• unlike Suzuki coupling, no base is required.
• a wide range of functional group tolerance , halide substrate with
NO2, CN, OMe, COOR, COOH, even CHO groups are tolerated.
• The presence of air also does not affect the reaction.

Limitation:
• Limited use in pharmaceutical industry.
• Toxicity of tin compound.
Examples:
Mechanism
 Industrial application
Stille coupling is an important step in the total synthesis of the marine
alkaloid Ircinal A. Ircinal A is a known antitumor substance. Among these
are manzamine A, oxazolomycin and many other.

Oxazolomycin
manzamine A
 Buchwald-Hartwig C-N coupling reaction

The coupling of an aryl halide with amine forms aromatic

amines using Pd catalyst.

X = Br, I, OTf; R = alkyl, CN, C(O)Ph, C(O)NEt2; R’ = aryl, alkyl

 Examples

Tricylic indole is precursor for the synthesis of Makaluvamine C and Damirone A and B (Alkaloids found in marine sponges)
Mechanism
Industrial applications
 Negishi Coupling Reactions
• It involves the cross coupling reaction between the
organozinc compound and organic halide in
presence of Ni or Pd catalyst.
• Pd(0) is active catalyst in this reaction.
Examples
Mechanism
 Industrial application

Negishi et al. synthesized b-carotene in three steps, including two Negishi coupling reactions. Another representative
example of the utility of this method is the enantioselective synthesis of discodermolide, a potent inhibitor of tumor
cell growth and a polyketide natural product isolated from the Caribbean marine sponge Discodermia dissolute