Suzuki and Shapiro reaction

Organic Chemistry- Synthetic Reaction

1. SUZUKI & SHAPIRO REACTION SUBMITTED BY : SHALINEE CHANDRA 1 st YEAR, M.PHARM, 21032 SUBMITTED TO : Mr. ASHOK KUMAR YADAV SIR PHARMACEUTICAL CHEMISTRY UIPS,PANJAB UNIVERSITY

2. SUZUKI REACTION In 1979, A. Suzuki and N. Miyaura reported a stereoselective synthesis of Arylated (E)-alkenes by cross-coupling reaction between organoboron compounds with organic halides or triflates This palladium-catalyzed cross-coupling reaction that forms carbon-carbon sigma bond and known as Suzuki cross-coupling reaction ( Commonly used for synthesizing biaryl compounds ) GENERAL SCHEME

3. MECHANISM

4. MECHANISM STEP1 – OXIDATIVE ADDITION - The rate determining step of the catalytic cycle in which an organic halide couples to the Palladium catalyt to form organopalladium complex[Pd(0)-species to form Pd(II); as two groups add to the metal] STEP2 – Exchange of the anion attached to the palladium for the anion of the base; Hydroxide attacks Pd, kicking off X

5. STEP 3 – TRANSMETALLATION - Lewis base (OH⁻) attacks the Lewis acid (B) These Pd(II) and the alkylborate complex state is most unstable and thus it will remove the R group(carbon); thus Carbon attaches to a metal because of closer electronegativity Electronegativity values: C=2.5, B=2.0, Pd=2.4

6. STEP 4 – Reductive elimination- The final step that forms the C-C sigma bond and also regenerates the Palladium catalyst[ Pd(0) ] so that it can participate again in catalytic cycle The order of reductive elimination is as follows : Ar-Ar > Ar -R > R-R

7. DISADVANTAGES Mild reaction conditions and commercial availability of many boronic acids Inorganic by-products is easily removed , suitable for industrial processes Boronic acids are much less toxic and safe than organostannanes Starting materials tolerate a wide variety of functional groups , and unaffected by water Coupling is generally stereo- and regioselective ADVANTAGES Generally aryl halides react sluggishly By-products (self-coupling Pdts .) are formed due to solvent-dissolved oxygen Coupling products of Phosphine -bound aryls often formed Reaction proceeds in presece of base, side reactions like racemization of optically active compounds or aldol condensations occur ADVANTAGES & DISADVANTAGES

8. The natural anti tumour product Epothilone A was synthesized in laboratory using Suzuki Cross Coupling Reaction. SYNTHETIC APPLICATIONS

9. The formal total synthesis of Oximidine (polyunsaturated 12-membered macrolactone core) was done by intramolecular Suzuki-type cross-coupling

10. The key step in total synthesis of Myxalamide A,Was Suzuki Cross-Coupling between (E)-vinylborane and a (Z)-iodotriene

11. In Valsartan , the biaryls can easily be prepared through Suzuki reaction

12. Xenbucin 1,an analgesic drug, was synthesized in 4 steps using two different routes, the biaryl fragment could successfully be produced via a Pd/C catalysed Suzuki coupling

13. Boscalid , a fungicide is prepared via Suzuki reaction

14. SHAPIRO REACTION Discovered by Robert H. Shapiro in 1967 Involves the base catalysed decomposition of tosyl hydrazones of aldehyde and ketones (having alpha hydrogen) into olefins by reacting with organolithium compound as base (usually two equivalent of MeLi or BuLi ) in ether, hexane, or tetramethylenediamine carried out at -78°C

15. GENERAL SCHEME Tosyl hydrazone is a functional group with the general structure RR’C=N-NH-Ts , where Ts is tosyl group or Toluene sulfonyl group (used as ‘ Protecting Group ’ for alcohols and amines to obtain chemoselectivity in a multistep reaction) Tosyl hydrazone Shapiro reaction provides good yields of alkenes without side reactions and less highly substituted alkene is predominantly formed

16. This reaction is similar to Bamford Steven reaction where bases such as NaOMe , LiH , NaH , NaNH ₂ etc are used Major difference is that Shapiro reaction yield less substituted olefins as kinetic product (predominates reaction at low temperature) while Bamford Stevens reaction yields more substituted olefins as thermodynamic product (predominates reaction at higher temperature)

17. MECHANISM Deprotonation of –NH proton from aryl sulfonyl hydrazone happens, reaction of tosylhydrazone with a strong base (usually metal- alkoxides ) results in the formation of a diazo compound In case of Shapiro reaction , two equivalents of alkyllithium reagent deprotonate the tosylhydrazone both at the nitrogen and the α -carbon and an alkenyllithium intermediate is formed via a carbanion mechanism . The protonation of the alkenyllithium gives rise to the alkene

18. Example of Cyclohexanone -

19. Bamford Steven Reaction mechanism In aprotic condition, initially formed diazo compound loses a molecule of nitrogen and forms a carbene intermediate , that undergoes a [1,2]-H shift and gives rise to alkene

20. Preferable substitutions for the two different reactions are Shapiro reaction Bamford-Steven reaction

21. What will be the major product formed in the following reaction ? ANSWER : OPTION 1 PRACTICE QUESTION

22. SYNTHETIC APPLICATIONS Synthesis of an allylic alcohol, which is an intermediate in synthesis of Mequitazine,an H1 antihistaminic used to treat allergies and rhinitis

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24. Shapiro reaction is involved in formation of ring B in the Nicolaou Taxol total synthesis