F C Reaction

8/8/2019 F C Reaction

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New developments in theNew developments in the

FriedelFriedelCrafts alkylationCrafts alkylation FromFromgreen chemistry to asymmetricgreen chemistry to asymmetric

catalysiscatalysis

MagnusMagnus RuepingRueping-- Institute of Organic Chemistry,Institute of Organic Chemistry,GermanyGermany

BorisBoris J.J. NachtsheimNachtsheim-- Department of Biological ChemistryDepartment of Biological Chemistryand Molecular Pharmacology, Harvard Medical School, USAand Molecular Pharmacology, Harvard Medical School, USA

ReceivedReceived 10 Sep 200910 Sep 2009AcceptedAccepted 17 Nov 200917 Nov 2009

PublishedPublished 20 Jan 201020 Jan 2010


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Introduction:Introduction:

In 1887, Charles Friedel and James Mason CraftsIn 1887, Charles Friedel and James Mason Craftsisolated amylbenzene after the treatment ofisolated amylbenzene after the treatment ofamyl chloride with AlClamyl chloride with AlCl33 in benzene.in benzene.

This was not only one of the first descriptions ofThis was not only one of the first descriptions of

a Lewis acid used in organic synthesis, but alsoa Lewis acid used in organic synthesis, but alsothe first example.the first example.

Other Lewis acidsOther Lewis acids-- BFBF33, BeCl, BeCl22, TiCl, TiCl44, SbCl, SbCl55 ororSnClSnCl44 also used.also used.

Benzene amyl chloride Amyl benzene


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Most often used metal salts for catalytic FCMost often used metal salts for catalytic FCalkylations and hydroarylations of arenesalkylations and hydroarylations of arenes


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Drawbacks of Classical FriedelDrawbacks of Classical Friedel

Crafts conditions:Crafts conditions:

Stoichiometric or super stoichiometricStoichiometric or super stoichiometric

amounts of catalyst and toxic benzylamounts of catalyst and toxic benzylhalides.halides.

vast amounts of salt side products.vast amounts of salt side products.

Side productsSide products-- HClHCl


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Requirement for further research:Requirement for further research: Environmentally benign substratesEnvironmentally benign substrates--

greener processesgreener processes-- benzylbenzyl--, propargyl, propargyl--and allyl alcohols: water as side product,and allyl alcohols: water as side product,

or styrenes: no side products .or styrenes: no side products . Low catalyst loadings highly desirableLow catalyst loadings highly desirable


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The FC alkylation with benzyl alcoholsThe FC alkylation with benzyl alcohols AnAnefficient approach to 1,1efficient approach to 1,1--diarylalkanesdiarylalkanes

1,11,1--Diarylalkanes are important building blocksDiarylalkanes are important building blocksfor the synthesis of many pharmaceuticals,for the synthesis of many pharmaceuticals,

LetrazoleLetrazole-- Aromatase inhibitorAromatase inhibitor-- treatment oftreatment of

ovarian and breast cancer.ovarian and breast cancer. (Aromatase(Aromatase-- enz synthesizingenz synthesizingestrogen)estrogen)

PhenprocoumonePhenprocoumone-- Thrombosis prophylaxisThrombosis prophylaxis--treatment of blood clots.treatment of blood clots.

DimetindeneDimetindene-- Histamine agonistHistamine agonist-- treatment oftreatment ofallergy.allergy.

AndAnd agroagro-- Haplopappin and fine chemicals.Haplopappin and fine chemicals.


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1,1-diarylalkanes with biological activity


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.

In 1986, Uemura et al. investigated thechlorination of benzyl- and alkyl alcoholsmediated by SeCl4 and TeCl4

Initially reported TeCl4-mediated FC

alkylation of 1-phenylethanol with toluene.


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In 1996, systematic investigations ofIn 1996, systematic investigations of

catalytic FC benzylations were performedcatalytic FC benzylations were performedby Fukuzawaby Fukuzawa

Sc(OTf)3Sc(OTf)3--catalyzed (as a water and aircatalyzed (as a water and air

tolerant catalyst) FC benzylation of arenestolerant catalyst) FC benzylation of arenes


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In 2005 Beller et al. systematically testedIn 2005 Beller et al. systematically testedthe activity of various Lewisthe activity of various Lewis-- and Brnstedand Brnstedacids in FC benzylations.acids in FC benzylations.

HAuClHAuCl44, IrCl, IrCl33, [MesW(CO), [MesW(CO)33], RhCl], RhCl33,,HH22PdClPdCl44, H, H22PtClPtCl66 and FeCland FeCl3,3, the latethe late

transition metals were the most effective.transition metals were the most effective.

FeClFeCl33(10(10 mol%), in particular, is anmol%), in particular, is anattractive alternative to rareattractive alternative to rare--earth triflatesearth triflates

since it is nonsince it is non--toxic, cheap and readilytoxic, cheap and readilyavailable.available.


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Even fairly unstable thiopheneEven fairly unstable thiophene-- and furanand furan--

22--carbaldehyde derived benzyl alcohols,carbaldehyde derived benzyl alcohols,cyano(phenyl)methyl acetate or 3cyano(phenyl)methyl acetate or 3--hydroxyhydroxy--33--phenylpropanoates and benzylphenylpropanoates and benzylmethyl ethers have been successfullymethyl ethers have been successfullyapplied as benzylation reagentsapplied as benzylation reagents


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Gold(III) as a catalyst for synthesis ofGold(III) as a catalyst for synthesis ofbeclobrate, a well known fibric acid derivativebeclobrate, a well known fibric acid derivativewith a potent hypolipidemic activity. Thewith a potent hypolipidemic activity. Thestraightforward synthesis was accomplished bystraightforward synthesis was accomplished byreaction of readily availablereaction of readily available pp--chlorobenzylchlorobenzylacetate (12) with 2acetate (12) with 2--methylmethyl--22--phenoxybutyratephenoxybutyrate(13) to give beclobrate (14) in 90% yield.(13) to give beclobrate (14) in 90% yield.However, 10 mol% of HAuClHowever, 10 mol% of HAuCl44 had to be used.had to be used.


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monomono--substituted 1,3substituted 1,3--diketones requiresdiketones requiresstoichiometric amounts of a base and a toxicstoichiometric amounts of a base and a toxic

alkyl halide the development of an efficientalkyl halide the development of an efficientenvironmentally benign route to 2environmentally benign route to 2--alkylatedalkylatedpentanedionespentanediones

Ex: Iron(III)Ex: Iron(III)--catalyzed onecatalyzed one--step synthesis ofstep synthesis ofphenprocoumon (20), an anticoagulant of thephenprocoumon (20), an anticoagulant of the

warfarinwarfarin--class that is widely used in thrombosisclass that is widely used in thrombosisprophylaxis. Simply starting from 4prophylaxis. Simply starting from 4--hydroxycoumarin (18) and 1hydroxycoumarin (18) and 1--phenylpropanphenylpropan--11--olol(19), phenprocoumon (20) was obtained in 94%(19), phenprocoumon (20) was obtained in 94%yieldyield


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Bismuth salts (Lewis acid) have emerged asBismuth salts (Lewis acid) have emerged ascheap, noncheap, non--toxic, and readily available catalyst.toxic, and readily available catalyst.

Certain bismuth salts are compatible with air andCertain bismuth salts are compatible with air andmoisturemoisture

Rueping group decided to examine the bismuthRueping group decided to examine the bismuth--

catalysed arylation and alkylation of benzylcatalysed arylation and alkylation of benzylalcohols. With small amounts of Bi(OTf)3 (0.5alcohols. With small amounts of Bi(OTf)3 (0.5mol%) they were able to benzylate arenesmol%) they were able to benzylate arenesbearing methyl, methoxy or hydroxybearing methyl, methoxy or hydroxy

functionalities as well as heteroarenes, includingfunctionalities as well as heteroarenes, includingthiophenes or 3thiophenes or 3--methylindolemethylindole

parapara//orthoortho//metameta regioselectivity observed.regioselectivity observed.


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Bi(OTf)3Bi(OTf)3--catalyzed FC alkylation of benzylcatalyzed FC alkylation of benzyl

alcohols developed by Rueping et al.alcohols developed by Rueping et al.


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Intramolecular reaction: biaryl benzyl alcohol 23Intramolecular reaction: biaryl benzyl alcohol 23led to substituted fluorenes 24 which haveled to substituted fluorenes 24 which have

shown to be valuable scaffolds for blue lightshown to be valuable scaffolds for blue lightemitting polymersemitting polymers

(A)(A) Bi(OTf)3Bi(OTf)3--

catalyzedcatalyzedintramolecular FCintramolecular FCalkylation as analkylation as anefficient route toefficient route tosubstituted fulvenes.substituted fulvenes.(B)(B) NanostructuredNanostructured

MoO3 mediatedMoO3 mediatedintramolecular FCintramolecular FCalkylation.alkylation.


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Catalytic FriedelCatalytic FriedelCrafts allylationCrafts allylation::

Allylated arenes represent attractiveAllylated arenes represent attractiveprecursors for organic synthesis as thereprecursors for organic synthesis as thereare several possibilities for furtherare several possibilities for furthertransforming the exocyclic double bonds.transforming the exocyclic double bonds.

FCFC--typetypealkylations withalkylations withallyl alcohols asallyl alcohols asalkylatingalkylating

reagentsreagents linear vs.linear vs.branchedbranchedproductproductformationformation..


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Chan et al developed an efficient Au(III)Chan et al developed an efficient Au(III)--catalyzed FC arylation of cinnamyl alcohols 64catalyzed FC arylation of cinnamyl alcohols 64

and electronand electron--rich arenes such as 2,6rich arenes such as 2,6--dimethylphenol 65.dimethylphenol 65.

With 5 mol% of AuClWith 5 mol% of AuCl33 catalyst at roomcatalyst at roomtemperature, the desired allylated arenes andtemperature, the desired allylated arenes andheteroarenes 66 were isolated in good yieldsheteroarenes 66 were isolated in good yieldsafter short reaction times. Beside cinnamylafter short reaction times. Beside cinnamylalcohols 66a and 66b, 1alcohols 66a and 66b, 1--arylated allyl alcoholsarylated allyl alcoholscould be used in this transformation giving, forcould be used in this transformation giving, forexample, the benzylated dihydronaphthaleneexample, the benzylated dihydronaphthalene66c and cyclohexanone 66d in good yield66c and cyclohexanone 66d in good yield


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Au(III)Au(III)--catalyzed cinnamylation of arenescatalyzed cinnamylation of arenes


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THE ENDTHE END

F C Reaction

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