1. Palladium Catalyzed Annulation Bei Zhao 59-6362003-11-21

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. 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) 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. Few of those processes were very general in scope.

4. Introduction Richard C. Larock, Department of Chemistry, Iowa State University Richard C. Larock, Department of Chemistry, Iowa State University From 1980’s to 2002 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. 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 dienes,alkenes,alkynes Merits: Catalytic amounts of PdCatalytic amounts of Pd Good yieldsGood yields VersatileVersatile appropriately functionalized aryl halide,appropriately functionalized aryl halide, vinylic halides orvinylic halides or triflatestriflates + Pd cat Heterocyclecarbocycle

7. Application on Liquid Crystal Synthesis Offered various annulation routes for synthesizing discotic and calamatic liquid crystal molecules. 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) Reduction of the palladium(II) salt to Pd(0) Oxidative addition of the aryl halide to Pd(0)--- Rate determining step 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 Arylpalladation of the carbon – carbon double bond to initially produce a σ- allylpalladium intermediate, which rapidly rearranges to the more Stable π-allylpalladium intermediate, intermediate, which rapidly rearranges to the more Stable π-allylpalladium intermediate, Nucleophilic displacement of palladium by the internal nucleophile Nucleophilic displacement of palladium by the internal nucleophile The displacement step may involve either backside attack of the nucleophile on the π -allylpalladium carbon 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). 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. The nature of the Pd catalyst don ’ t have a major effect on the annulation. Pd(OAc)2 readily available,preferable Pd(OAc)2 readily available,preferable Pd(DBA)2 (DBA=dibenzylideneacetone) Pd(DBA)2 (DBA=dibenzylideneacetone) Pd(PPh3)4 Pd(PPh3)4 Polar solvents N,N-dimethylformamide Polar solvents N,N-dimethylformamide 1,3-Diene has to be excess, because it ’ s volatile 1,3-Diene has to be excess, because it ’ s volatile Temperature 80-120°C Temperature 80-120°C Rate determining step oxidative addition of the aryl halides to palladium(0) Rate determining step oxidative addition of the aryl halides to palladium(0) lower temp ------ XH= electron- withdrawing group(eg.-COOH,-NO3) lower temp ------ XH= electron- withdrawing group(eg.-COOH,-NO3) higher temp-------XH=electron-rich group(eg.-OH,-NH2) higher temp-------XH=electron-rich group(eg.-OH,-NH2)

11. General condition Base mild bases e.g. potassium or sodium acetate, carbonate, bicabonate … Base mild bases e.g. potassium or sodium acetate, carbonate, bicabonate … Presence of triphenylphosphine Presence of triphenylphosphine Chloride source Chloride source LiCl or n-Bu 4 NCl LiCl or n-Bu 4 NCl one equivalent per aryl/ vinylic halide/ triflate one equivalent per aryl/ vinylic halide/ triflate coordinate strongly to the Pd(0) to enhance its ability to undergo oxidative addition coordinate strongly to the Pd(0) to enhance its ability to undergo oxidative addition

12. Regioselectivity Generally very high. Generally very high. Less hindered terminal double bond is favored. 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 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. The double bond ends up in the more thermodynamically stable configuration. Electron-withdrawing substitutent is favored. Electron-withdrawing substitutent is favored. Sometimes 1,4-annulation of a 1,3-diene can also happen.eg. 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 Unsaturated Cyclopropanes and Cyclobutanes

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. 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. However, the use of silylalkynes and subsequent electrophilic substitution or desilylation greatly expands the scope of this synthesis.Eg.

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

21. Internal annulation

22. Conclusion Pd catalyzed annulation Employs only catalytic amounts of palladium Employs only catalytic amounts of palladium Relatively simple starting materials Relatively simple starting materials Generate organopalladium compounds from simple aryl or vinylic halides or triflate by oxidative addition Generate organopalladium compounds from simple aryl or vinylic halides or triflate by oxidative addition Mild conditions 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, Mark J. Doty,Qingping Tian, and John M. Zenner.J. Org. Chem.62(1997) 7536 Richard C. Larock. J.Orgmet. Chem. 576(1999)111 Richard C. Larock. J.Orgmet. Chem. 576(1999)111 Dawei Yue and Richard C. Larock.J. Org. Chem.67(2002) 1905 Dawei Yue and Richard C. Larock.J. Org. Chem.67(2002) 1905

24. Thanks for your attention! 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.