Kumada cross coupling reaction

C-C bond generation in Organic Chemistry

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2. KUMADA CROSS-COUPLING REACTION Dr. Shahid Rasool   Kumada Cross-coupling reaction   CHEM5128 Advanced Named Reactions   2

3. Key Concepts Kumada Cross-Coupling reactions Discussion of reacting species, catalysts, solvents Mechanism of reaction Explanation of mechanism step by step Synthetic applications 3

4. Kumada Cross-coupling Reaction: Kumada cross-coupling reaction is also known as Kharasch cross-coupling reaction. Ni or Pd catalyzed cross-coupling reaction Kumada cross-coupling reaction is between Grignard reagent and organic halides, triflate etc. Overall reaction is given as, THF, DEE

5. Similar Cross-coupling Reactions: This reaction is similar to following reactions which also Ni or Pd, Negishi cross-coupling reaction ( Organozinc reagents, RZnX ) Stille cross-coupling reaction ( Organostannanes reagents, R 4 Sn) Hiyama cross-coupling reaction ( Organosilicons , RSiF 3 ) Suzuki cross-coupling reaction ( Organoboranes , R 3 B)

6. Alkyl halides (R-X): R = Alkyl, Vinyl, Aryl groups High rates have been observed for vinyl or aryl groups A limitation for alkyl group is that there are chances of elimination if there is β -hydrogen. X = Cl , Br, I Order of rate = I > Br > Cl as bond energy R-I > R-Br > R- Cl

7. Triflates and tosylates : R = Alkyl, Vinyl, Aryl groups If X = OTf then called Triflates , If X = OTs then called Tosylates Good leaving groups due to resonance stabilized anions. The distribution of charge on large number of atoms provides stability because it becomes easy for the medium molecules to solvate it.

8. Grignard Reagent (R-Mg-X): R = Alkyl, Vinyl, Aryl groups X = Cl , Br, I, OTf , Ots Highly reactive reagent due to C-Mg bond polarity C-Mg bond having less bond energy as compared to Mg-X bond, so it is easily broken. Poor functional group tolerance due to high reactivity Low temperature synthesis due to high reactivity and low activation energy

9. Catalysts: Nickel (Ni) or Palladium (Pd) Platinum is also of same group (VIIIB) but too expensive Complexes of these metals are used e.g. L 2 M L = bidentate phosphine ligands e.g. dppe , dppp dppe = 1,2-Bis( diphenylphosphino )ethane dppp = 1,2-Bis( diphenylphosphino )propane Pd complexes are air sensitive (Argon/N 2 atmosphere)

10. Solvent: Tetrahydrofuran (THF) or Diethylether (DEE) Ethereal solvents are used because (1) Dry ether avoid reaction of R-Mg-X with moisture (2) Stabilize R-Mg-X through complex formation This can be justified by electronic configuration of magnesium, 12 Mg = 1s 2 2s 2 2p 6 3s 2 3p x 3p y 3p z (Ground state) 12 Mg = 1s 2 2s 2 2p 6 3s 1 3p x 1 3p y 3p z (Excited state)

11. Overall Pd-catalyzed Mechanism:

12. Steps of mechanism: Four steps of mechanism are (1) Oxidative addition (2) Transmetallation (3) Isomerization (4) Reductive elimination

13. Step-1, Oxidative addition: This step is known to follow concerted mechanism of addition. Pd(0) is oxidized to Pd(II) R-X is added in concerted way Both ‘R’ and ‘X’ are attached to ‘Pd’ through its primary valency . Secondary valency ‘4’ is already justified by bidendate ligands .

14. Step-2, Transmetallation : It is interchanging of metals attached to different groups. Irreversible due to thermodynamic (favor based on electronegativity ) or kinetic (favor if empty orbitals in both metals) reasons Redox metallation Ligand exchange Transmetallation in Kumada cross-coupling reaction

15. Step-3, Isomerization : Isomerization involves the rearragement of complex in such a way that R- groups move in adjacent position This step is thought to be completed along with the last step of transmetallation .

16. Step-4, Reductive elimination: This step is also known to follow concerted mechanism of elimination. Pd(II) is reduced to Pd(0) R-R 1 is eliminated from the complex in a concerted way

17. Overall Ni-catalyzed Mechanism:

18. Stereo-selectivity: For vinylic alkyl halides, cis -R-X results into cis -product For vinylic alkyl halides, trans-R-X results into trans-product For R-Mg-X, cis or trans-R results into a mixture of cis and trans-products

19. Enantio -selectivity: Asymmetric synthesis by Pladium catalyst with chiral ligands results into one enantiomeric product (>90%) A: [ Methoxyalkyl ( ferrocenyl )] monophosphine B: bis-oxazoline

20. Synthesis of Aliskiren (hypertension drug): Synthesis of polythiophenes (organic solar cells, LED) :