Palladium Catalyzed Palladium Catalyzed AnnulationAnnulation

Bei ZhaoBei Zhao

59-63659-636

2003-11-212003-11-21

SummarySummary

.Introduction.Introduction

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

. Conclusion. Conclusion

IntroductionIntroduction

Palladium has been proved extraordinarily Palladium has been proved extraordinarily useful for the synthesis of a wide variety of useful for the synthesis of a wide variety of heterocycles and carbocycles.heterocycles and carbocycles.

Prior to 1990, there were a number of reports of Prior to 1990, there were a number of reports of the palladium-catalyzed synthesis of the palladium-catalyzed synthesis of heterocycles by appending a heteroatom-heterocycles by appending a heteroatom-containing unit onto existing functionality containing unit onto existing functionality (heteroannulation) (heteroannulation)

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

IntroductionIntroduction

Richard C. Larock,Richard C. Larock, Department of Department of Chemistry, Iowa State UniversityChemistry, Iowa State University

From 1980’s to 2002From 1980’s to 2002 The palladium-catalyzed annulation of The palladium-catalyzed annulation of

cyclic and bicyclic alkenes, unsaturated cyclic and bicyclic alkenes, unsaturated cyclopropanes and cyclobutanes, cyclopropanes and cyclobutanes, allenesallenes, , 1,3-1,3-and 1,4-and 1,4-dienesdienes, as well as , as well as internal internal alkynesalkynes, by appropriately-substituted aryl , by appropriately-substituted aryl or vinylic halides and triflates provides a or vinylic halides and triflates provides a very efficient, yet versatile route to a wide very efficient, yet versatile route to a wide variety of heterocycles and carbocycles.variety of heterocycles and carbocycles.

Previous methods for annulationPrevious methods for annulation

Drawbacks:

• using stoichiometric amounts of Palladium salts

• toxic organomercurials

Annulation by Palladium Catalyst Annulation by Palladium Catalyst

dienes,alkenes,dienes,alkenes,

alkynesalkynes

Merits:Merits:•Catalytic amounts of PdCatalytic amounts of Pd•Good yieldsGood yields•VersatileVersatile

•appropriately appropriately functionalized functionalized aryl halide, aryl halide, •vinylic halides orvinylic halides or•triflatestriflates

+ Pd catHeterocycleHeterocycle

carbocyclecarbocycle

ApplicationApplication onon LiquidLiquid CrystalCrystal SynthesisSynthesis

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

X

X=O,N

Reaction with 1,3-DienesReaction with 1,3-Dienes

MechanismMechanism Reduction of the palladium(II) salt to Reduction of the palladium(II) salt to

Pd(0)Pd(0)

Oxidative addition of the aryl halide to Oxidative addition of the aryl halide to

Pd(0)--- Pd(0)--- Rate determining step Rate determining step

Arylpalladation of the carbon–carbon Arylpalladation of the carbon–carbon

double bond to initially produce a double bond to initially produce a σσ--

allylpalladiumallylpalladium

intermediate, which rapidly rearranges to intermediate, which rapidly rearranges to

the more Stable the more Stable ππ-allylpalladium -allylpalladium

intermediate,intermediate,

Nucleophilic displacement of palladium by Nucleophilic displacement of palladium by

the internal nucleophilethe internal nucleophile

The displacement step may involve either The displacement step may involve either

backside attack of the nucleophile on the backside attack of the nucleophile on the

ππ-allylpalladium carbon-allylpalladium carbon

or frontal attack at the metal, followed by or frontal attack at the metal, followed by

reductive elimination of Pd(0).reductive elimination of Pd(0).

General ConditionsGeneral Conditions The nature of the Pd catalystThe nature of the Pd catalyst don’t have a don’t have a

major effect on the annulation.major effect on the annulation. Pd(OAc)2 readily available,preferablePd(OAc)2 readily available,preferable Pd(DBA)2 (DBA=dibenzylideneacetone)Pd(DBA)2 (DBA=dibenzylideneacetone) Pd(PPh3)4Pd(PPh3)4 Polar solventsPolar solvents N,N-dimethylformamide N,N-dimethylformamide 1,3-Diene1,3-Diene has to be has to be excessexcess, because it’s , because it’s

volatilevolatile Temperature Temperature 80-120°C 80-120°C Rate determining step oxidative addition of the aryl halides to Rate determining step oxidative addition of the aryl halides to

palladium(0) 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)

General conditionGeneral condition

Base Base mild bases e.g. potassium or sodium mild bases e.g. potassium or sodium

acetate, carbonate, bicabonate… acetate, carbonate, bicabonate… Presence of triphenylphosphinePresence of triphenylphosphine Chloride sourceChloride source

LiCl orLiCl or n-Bun-Bu44NCl NCl

one equivalent per aryl/ vinylic halide/ triflateone equivalent per aryl/ vinylic halide/ triflate

coordinate strongly to the Pd(0) to enhance its coordinate strongly to the Pd(0) to enhance its

ability to undergo oxidative additionability to undergo oxidative addition

RegioselectivityRegioselectivity 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 Exceptionally, annulations of phenolic substrates onto

isoprene and derivatives have been observed to give 8–12% isoprene and derivatives have been observed to give 8–12% of the product from annulation of the more highly of the product from annulation of the more highly substituted double bondsubstituted double bond

The double bond ends up in the more thermodynamically The double bond ends up in the more thermodynamically stable configuration. stable configuration.

Electron-withdrawing substitutent is favored.Electron-withdrawing substitutent is favored. Sometimes 1,4-annulation of a 1,3-diene can also Sometimes 1,4-annulation of a 1,3-diene can also

happen.eg.happen.eg.

The effect of oxygen substituent

Reaction with1,2-dieneReaction 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

Reaction with UnsaturatedReaction with Unsaturated CyclopropanesCyclopropanes andand CyclobutanesCyclobutanes

Reaction with Cyclic and bicyclic alkenesReaction with Cyclic and bicyclic alkenes

•Proceed via π-allylpalladiumintermediates.

•Yield are only modest

Reaction with AlkynesReaction with Alkynes

Previous method:•Difficult to control•Stoichiometric amounts of Pd•Two steps to effect overall annulationNew method:•Catalytic amounts of Pd•One step

MechanismMechanism

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

Limitation and developmentLimitation and development

Only alkynes substituted with Only alkynes substituted with aryl, silyl, carbonylaryl, silyl, carbonyl or or hindered alkylhindered alkyl groups work well. groups work well.

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

Eg.Eg.

Internal annulationInternal annulation

Eg.used to synthesis of 2,3-disubstituted Eg.used to synthesis of 2,3-disubstituted benzothiophenebenzothiophene

First use Sonogashira coupling, then First use Sonogashira coupling, then annulate.annulate.

Get very high yield.Get very high yield.

InternalInternal annulationannulation

ConclusionConclusion

Pd catalyzed annulationPd catalyzed annulation

Employs only catalytic amounts of palladiumEmploys only catalytic amounts of palladium Relatively simple starting materialsRelatively simple starting materials Generate organopalladium compounds from Generate organopalladium compounds from

simple aryl or vinylic halides or triflate by simple aryl or vinylic halides or triflate by oxidative addition oxidative addition

Mild conditionsMild conditions

ReferenceReference

Richard C. Larock, Mark J. Richard C. Larock, Mark J. Doty,Qingping Tian, and John M. Doty,Qingping Tian, and John M. Zenner.J. Org. Chem.62(1997) 7536Zenner.J. Org. Chem.62(1997) 7536

Richard C. Larock. J.Orgmet. Chem. Richard C. Larock. J.Orgmet. Chem. 576(1999)111576(1999)111

Dawei Yue and Richard C. Larock.J. Dawei Yue and Richard C. Larock.J. Org. Chem.67(2002) 1905Org. Chem.67(2002) 1905

Thanks for your attention!Thanks for your attention!

desilylation

1,4-Dinene1,4-Dinene

eg.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.