Palladium Catalyzed Annulation

1. Palladium Catalyzed Annulation Bei Zhao 59-636 2003-11-21

2. Summary .Introduction . Annulation with 1,3-Diene, 1,2-Diene,Unsatured cyclopropanes and cyclobutanes, cyclic and bicyclic alkenes, Alkynes . Conclusion

3. Introduction • Palladium has been proved extraordinarily useful for the synthesis of a wide variety of heterocycles and carbocycles. • Prior to 1990, there were a number of reports of the palladium-catalyzed synthesis of heterocycles by appending a heteroatom-containing unit onto existing functionality (heteroannulation) • Few of those processes were very general in scope.

4. Introduction • Richard C. Larock,Department of Chemistry, Iowa State University • From 1980’s to 2002 • The palladium-catalyzed annulation of cyclic and bicyclic alkenes, unsaturated cyclopropanes and cyclobutanes, allenes, 1,3-and 1,4-dienes, as well as internal alkynes, by appropriately-substituted aryl or vinylic halides and triflates provides a very efficient, yet versatile route to a wide variety of heterocycles and carbocycles.

5. Previous methods for annulation • Drawbacks: • using stoichiometric amounts of Palladium salts • toxic organomercurials

6. Annulation by Palladium Catalyst • appropriately functionalized aryl halide, • vinylic halides or • triflates Heterocycle carbocycle + dienes,alkenes, alkynes Pd cat • Merits: • Catalytic amounts of Pd • Good yields • Versatile

7. ApplicationonLiquidCrystalSynthesis • Offered various annulation routes for synthesizing discotic and calamatic liquid crystal molecules.

8. Reaction with 1,3-Dienes

9. Mechanism • Reduction of the palladium(II) salt to Pd(0) • Oxidative addition of the aryl halide to Pd(0)--- Rate determining step • Arylpalladation of the carbon–carbon double bond to initially produce a σ-allylpalladium intermediate, which rapidly rearranges to the more Stable π-allylpalladium intermediate, • Nucleophilic displacement of palladium by the internal nucleophile • The displacement step may involve either backside attack of the nucleophile on the π-allylpalladium carbon • or frontal attack at the metal, followed by reductive elimination of Pd(0).

10. General Conditions • The nature of the Pd catalyst don’t have a major effect on the annulation. Pd(OAc)2 readily available,preferable Pd(DBA)2 (DBA=dibenzylideneacetone) Pd(PPh3)4 • Polar solvents N,N-dimethylformamide • 1,3-Diene has to be excess, because it’s volatile • Temperature 80-120°C Rate determining step oxidative addition of the aryl halides to palladium(0) lower temp ------ XH= electron- withdrawing group(eg.-COOH,-NO3) higher temp-------XH=electron-rich group(eg.-OH,-NH2)

11. General condition • Base mild bases e.g. potassium or sodium acetate, carbonate, bicabonate… • Presence of triphenylphosphine • Chloride source LiCl orn-Bu4NCl one equivalent per aryl/ vinylic halide/ triflate coordinate strongly to the Pd(0) to enhance its ability to undergo oxidative addition

12. Regioselectivity • Generally very high. • Less hindered terminal double bond is favored. • Exceptionally, annulations of phenolic substrates onto isoprene and derivatives have been observed to give 8–12% of the product from annulation of the more highly substituted double bond • The double bond ends up in the more thermodynamically stable configuration. • Electron-withdrawing substitutent is favored. • Sometimes 1,4-annulation of a 1,3-diene can also happen.eg. The effect of oxygen substituent

13. Reaction with1,2-diene • Provides an exciting new way to generate quaternary carbon centers, even adjacent quaternary centers • Can be extended to the formation of seven-, eight- and even nine-membered ring nitrogen heterocycles

14. Reaction with UnsaturatedCyclopropanesandCyclobutanes

15. Reaction with Cyclic and bicyclic alkenes • Proceed via π-allylpalladiumintermediates. • Yield are only modest

16. Reaction with Alkynes • Previous method: • Difficult to control • Stoichiometric amounts of Pd • Two steps to effect overall annulation • New method: • Catalytic amounts of Pd • One step

17. Mechanism • Arylpalladium formation, • Regioselective addition to the carbon–carbon triple bond of the alkyne, • Intramolecular palladium displacement

18. Limitation and development • Only alkynes substituted with aryl, silyl, carbonyl or hindered alkyl groups work well. • However, the use of silylalkynes and subsequent electrophilic substitution or desilylation greatly expands the scope of this synthesis. Eg.

20. Internal annulation • Eg.used to synthesis of 2,3-disubstituted benzothiophene • First use Sonogashira coupling, then annulate. • Get very high yield.

21. Internalannulation

22. Conclusion Pd catalyzed annulation • Employs only catalytic amounts of palladium • Relatively simple starting materials • Generate organopalladium compounds from simple aryl or vinylic halides or triflate by oxidative addition • Mild conditions

23. Reference • Richard C. Larock, Mark J. Doty,Qingping Tian, and John M. Zenner.J. Org. Chem.62(1997) 7536 • Richard C. Larock. J.Orgmet. Chem. 576(1999)111 • Dawei Yue and Richard C. Larock.J. Org. Chem.67(2002) 1905

24. Thanks for your attention!

26. desilylation

27. 1,4-Dinene eg. • successful on a variety of functionalized aryl halides and substituted acyclic and even cyclic 1,4-dienes. • The regioselectivity of this reaction is excellent.