1. METAL MEDIATED C-C And C-X COUPLING REACTIONS HECK REACTION STILLE REACTION

2. HECK REACTION  It is also called Mizoroki – Heck reaction.  The Heck reaction is the chemical reaction of an unsaturated halide with an alkene in the presence of a base and a palladium catalyst to form a substituted alkene.  It is named after Tsutomu Mizoroki and Richard F. Heck.  Heck was awarded the 2010 Nobel prize in chemistry, which he shared with Ei – ichi Negishi and Akira Suzuki for the discovery and development of this reaction.

4.  The original reaction by Tsutomu Mizoroki (1971) describes the coupling between iodobenzene and styrene in methanol to form Stilbene at 120 °C (autoclave) with Potassium acetate based and palladium Chloride catalysis.

5.  In 1972 Heck acknowledged the Mizoroki publication and detailed independently discovered work. The reaction conditions differ in catalyst used (palladium acetate) and catalyst loading (0.01 eq.), base used (a hindered amine) and lack of solvent.

6.  The general features of the reaction are:  1) it is best applied for the preparation of disubstituted olefins from monosubstituted ones;  2) the electronic nature of the substituents on the olefin only has limited influence on the outcome of the reaction; it can be either electron-donating or electron-withdrawing but usually the electron poor olefins give higher yields;  3) the reaction conditions tolerate a wide range of functional groups on the olefin component: esters, ethers, carboxylic acids, nitriles, phenols, dienes, etc., are all well- suited for the coupling, but allylic alcohols tend to rearrange;  4) the reaction rate is strongly influenceded by the degree of substitution of the olefin and usually the more substituted olefin undergoes a slower Heck reaction;

7.  6) the nature of the X group on the aryl or vinyl component is very important and the reaction rates change in the following order: I > Br ~ OTf >> Cl;  7) the R group in most cases is aryl, heteroaryl, alkenyl, benzyl, and rarely alkyl (provided that the alkyl group possesses no hydrogen atoms in the β-position), and these groups can be either electron-donating or electron-withdrawing;  8) the active palladium catalyst is generated in situ from suitable precatalysts (e.g., Pd(OAc)2, Pd(PPh3)4)  9) the reaction is not sensitive to water, and the solvents need not be thoroughly deoxygenated; and  10) the Heck reaction is stereospecific as the migratory insertion of the palladium complex into the olefin and the β- hydride elimination both proceed with syn stereochemistry

8. MECHANISM

9.  This coupling reaction is stereoselective with a propensity for trans coupling as the palladium halide group and the bulky organic residue move away from each other in the reaction sequence in a rotation step.  The Heck reaction is applied industrially in the production of naproxen and the sunscreencomponent octyl Methoxycinnamate.  The naproxen synthesis includes a coupling between a brominated naphthalene compound with ethylene.

11. STILLE REACTION  The Pd(0)-catalyzed coupling reaction between an organostannane and an organic electrophile to form a new C-C sigma bond is known as the Stille cross coupling.  The Stille reaction is a chemical reaction widely used in organic synthesis.  The reaction involves the coupling of two organic groups, one of which is carried as an organotin compound(also known as organostannanes).  A variety organic electrophiles provide the other coupling partner.

12.  These organostannanes are also stable to both air and moisture, and many of these reagents either are commercially available or can be synthesized.  However, these tin reagents tend to be highly toxic. X is typically a halide, such as cl, Br or I, yet pseudohalides such as Triflates and sulfonate and phosphate can also be used.  Due to these organotin reagent's stability to air and their ease of synthesis, the Stille reaction became common in organic synthesis.  The Stille reaction, named after the late John Kenneth Stille, is a palladium- catalyzed cross coupling reaction.

13. MECHANISM

14. Oxidative addition  The alkyl halide would first perform oxidative addition to the palladium in a concerted fashion, resulting in a 16-electron Pd(II) intermediate.  The cis square planer product is in a fast equilibrium with the trans product.  The bulky ligands used on the catalyst makes the trans product more thermodynamically stable, therefore most of the intermediate will isomerize into the trans product.

15. Transmetalation  The Stille coupling uses organostannane as a trans coupling reagent.  The tin is usually bound to allyl, alkenyl, or aryl groups. The tin and the R’ group will form a four-member ring with the palladium center and the halide, forming an 18- electron transition state.  Then the tin halide will leave and the R’ group stays bonded to palladium.

16. Reductive elimination  The two trans- R groups must first isomerize back into a cis- conformation, then it can undergo a concerted reductive elimination.  There are other two proposed mechanisms which involves the association or dissociation of the ligands.  An extra ligand can be bond to palladium, forming an 18-electron trigonal bipyramidal structure and forces the two R groups to the equatorial position, which is a suitable conformation for them to form C-C bonds.

17.  Another proposed mechanism is that one of the ligands will dissociate first to form a T-shape 14-electron intermediate, which is able to speed up the reductive elimination process.

18.  Stereochemistry is typically retained in Stille coupling.  Regioselectivity, as with most other coupling reactions is hard to control though optimizations have been found to control regioselectivity to some extent.  The Stille reaction has been used in the synthesis of a variety of polymers.  its use in organic synthesis and specifically, in the synthesis of natural products. EXAMPLES

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