3 Selected Reactions

7/31/2019 3 Selected Reactions

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TapioNevalainen

DrugSynthesisII

2011

Se ecte organic reactions

Crosscoupling reactions

Coupling reaction between aryl halides with copper (Ullmann reaction)

The Ullmann reaction is limited to electron deficient aryl halides and

requires harsh reaction conditions. Reaction is replaced by palladium

coupling reactions such as the Suzuki, Heck, Stille, Sonogashira reactions.


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Crosscoupling reactions

AkiraSuzuki,Eiichi Negishi andRichardHecksharetheNobelPrizeinChemistry2010forpalladiumcatalyzedcrosscouplingsin

8.2.2011Selected organic reactions / Tapio Nevalainen 3

More information:

http://static.nobelprize.org/nobel_prizes/chemistry/laureates/2010/Sciback_2010.pdf

PalladiumCatalyzedCouplingReactions

Pd0 catal stXR + M R' R'R

R, R' = aryl, vinyl

X = Br, I, OTf

M = B SuzukiSn StilleSi HiyamaZn Negishi

Mg Kumada

0

XAr R'+base

R'Ar

Heck reaction


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Generalizedmechanism

for

palladium

catalyzedcrosscouplingreactions

Mechanism oftheHeck reaction


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Palladiumcouplingreactions: SuzukiCoupling

PalladiumPalladium--catalysed cross coupling between organoboronic acid andcatalysed cross coupling between organoboronic acid and

halideshalides

Exam le: S nthesisS nthesis ofof losartanlosartan (( .. OrOr .. ChemChem. 1994,59, 8151. 1994,59, 8151--8156)8156)

Alkyls, alkenyls and alkynyls can also be used as a reaction partners . PotassiumAlkyls, alkenyls and alkynyls can also be used as a reaction partners . Potassium

trifluoroborates and organoboranes or boronate esters may be used in place oftrifluoroborates and organoboranes or boronate esters may be used in place of

boronic acids. Triflates (CFboronic acids. Triflates (CF33SOSO33--)) may also be used as coupling partnersmay also be used as coupling partners.

Heckreaction

The palladium-catalyzed C-C coupling between aryl halides or vinyl

halides and activated alkenes in the presence of a base

Example: Heck reaction of phenylbromides with (S)-N-acroyl-4-phenyl-2-oxazolidinone


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Theuse ofanintermolecular Heck reaction inthe

commercial synthesis ofmontelukast

(selective leukotriene receptor antagonist forthetreatment ofasthma)

O

CH3

NCl

HOCH2

O

O

I

+

NCl

HO

O

PdH I

Ln

Pd(OAc)2Et2N, MeCN, 85C

O

O

Top. Organomet. Chem. 2004, 7, 81 203

NCl

SCH

3

Montelukast (Singulair)

NCl

O HOOC

StilleCoupling C-C bond forming reaction between stannanes and halides or

pseudohalides, with very few limitations on the R-groups

R' '[Pd]R + SnBu3

RBase

+

J. Am. Chem. Soc., 1984, 106, 4630.

[Pd] = Pd(PPh3)4, PhCH2(PPh3)2ClR1 = alkynyl, alkenyl, aryl, allyl, benzyl, alkyl, acylR2 = alkenyl, allyl, benzyl, aryl, alkynylX = Cl, Br, I , OAc, OSO2CF3

XSnBu3


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TheSonogashirareaction

TheSonogashirareactionconsistsofthepalladiumcatalysedcouplingofcopperacetylidesandarylhalogenidestoyieldalkynylarenes(K.Sonogashira,Y.TohdaandN.Hagihara,TetrahedronLett.,1975,44674470)

X

+ R RPd-catalyst

Example: 2,4-Diamino-5-(2',5'-substituted benzyl)pyrimidines (J.(J. MedMed.. ChemChem., 47 (6), 1475., 47 (6), 1475--1486, 2004)1486, 2004)

-

Crosscouplingreactions NegishiCoupling

KumadaCoupling

HiyamaCoupling

R1

X +

MgX

R2

R1

R2[Kat] [Kat] = Pd(PPh3)4 or Ni(dppb)Cl2

R1 = aryl, vinyl

R2 = aryl, vinyl, alkylX = Cl > Br > I

Kumada. Bull. Chem. Soc. Jpn., 1976, 1958.

FukuyamaCoupling


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Mitsunobureaction The Mitsunobu reaction allows the conversion of primary and

secondary alcohols to esters, phenyl ethers, thioethers and variousother compounds. The nucleophile employed should be acidic.

Mitsunobu,O.;Wada,M.;Sano,T.J.Am.Chem.Soc. 1972,94,679;

Mitsunobu,O.Synthesis.1981,128.Hughes,D.L.Org.Reac. 1992,42,335656.

Mitsunobureaction:Mechanism


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Mitsunobureaction Inversion of configuration in the Mitsunobu reaction

Example 1:Example 1: Synthesis of MGLSynthesis of MGL--inhibitor Ninhibitor N--Arachidonyl MaleimideArachidonyl Maleimide

xamp e : ro e n yros ne p osp a ase n orsxamp e : ro e n yros ne p osp a ase n ors

TheWittigReaction (GeorgWittig,NobelPrizein1979)TheWittigReactionallowsthepreparationofanalkenebythe

reactionofanaldehydeorketonewiththeylidegeneratedfromaphosphoniumsalt

PhPh Ph

Ph Ph

oxaphosphetane

P+

H R'

HBase P+

H R'

P

H R'

RO

HP+

H

R'

Ph

Ph

Ph +R

R'

P

O

Ph PhPh

+Ph3P+

H

R'H

-O R

P

H

R'H

O R

Ph

PhPh

erythro betaine

ylidephosphorane

tt greact ongoesma n yv at eeryt ro eta ne nterme ate,whichleadstotheZalkene


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TheWittigReactionYlidesYlides thatthat possesspossess substituentsubstituent groupsgroups thatthat cancan undergoundergoconjugationconjugation soso as toas to stabilisestabilise thethe anionanion leadlead to theto the formationformation ofofEE--alkenesalkenes..

TheThe SchlosserSchlosser modificationmodification.. TheThe erythroerythro betainebetaine cancan bebe convertedconverted totothethe threothreo betainebetaine usingusing phenyllithiumphenyllithium atat lowlow temperaturetemperature ((formingforming aabetainebetaine ylideylide)) followedfollowed byby HClHCl. Upon. Upon workupworkup thisthis leadsleads to theto the EE--alkenealkene.. ((SchlosserSchlosser, M.;, M.; ChristmannChristmann, K. F., K. F. AngewAngew.. ChemChem.. IntInt. Ed. Engl.. Ed. Engl.1966, 5, 126)1966, 5, 126)

TheWittigReaction: TheWadsworthHornerEmmonsReaction

Thereactionofaldehydesorketoneswithstabilizedphosphorusylides(phosphonatecarbanions)leadstoolefinswithexcellentEselectivity.

ExampleExample:: SynthesisSynthesis ofof tropanetropane--likelike analoguesanalogues


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TheWittigReaction:Synthesisofacrivastine

(antihistamine)

CH3

CNNBr Br+

CH3

NBrNBr Li

CH3

CN

BuLi

CH3 CH3

N

N

CH3

BrNP+

Ph

Ph Ph

N

O

CH3

Br

1. BuLi

2.N O

Wittig

1

H3O+

t-BuOK

OEt

Acrivastine

N

N

N

NO

H

HN,N-dimetyyli-formamidi

2. NaOH

.

Horner-Wadsworth-Emmons

t-BuOK

EtO2C

HO2C

JuliareactionTheadditionofaphenylsulfonylcarbaniontoan

aldehydeorketoneleadstoalcohol,whichisesterifiedinsitu.Thereductiveeliminationleadsto(E)alkene.


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Peterson reaction

Preparation ofalkenes from silylcarbanions by acid orbaseinduced elimination.

Sulfurcontainingreagents

Thioacetals canactaseffectiveprotectinggroupsandcanbereducedbyRaneyNickeltoaffordthealkane.

CoreySeebachReactionSeebachUmpolung (reversalofpolarity):

carbonylgroupreactsasanelectrophileatcarbonwhichpolaritycanbereversedwhenthecarbonylgroupisconvertedintoathioacetal(dithiane).Acylprotoncanbeabstractedbynbutyllithiumtogenerate2lithio1,3dithiane,whichreactsasanucleophilewithe ec rop es ea y a esan ac c or es.


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Fluorinatedpharmaceuticals

Fluorinationagents

Nucleophilic agents

Electrophilic agents Reagents to introduce CF3 groups

More information: http://www.scripps.edu/chem/baran/images/grpmtgpdf/Su_May_08.pdf


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Fluorination

agents

RuppertPrakashtrimethyl(trifluoromethyl)silane

Oxidation Chemistry

TheSwernOxidation

MechanismMechanism


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OxidationChemistry

CoreyKimOxidation

allowoxidationabove25C

The BaeyerThe Baeyer--Villiger OxidationVilliger Oxidation

OxidationChemistry

DessMartinOxidation: TheDessMartinPeriodinane(DMP),offersselectiveandverymildoxidationofalcoholstoaldehydesor

ketones.

OppenauerOppenauer OxidationOxidation


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OxidationChemistry

Oxone =potassiummonopersulfate(KHSO5)

NefReaction:Theconversionofnitrocom oundsinto

Org. Lett., 2003, 5, 1031-1034

carbonyls

Synth. Commun., 1998, 28, 3057-3064.

R

2

R' R

O

R'

1. NaHPO4, MeOH

2. Oxone (0,7M H2O)

ReducingAgents

Selective Hydrogenations

OH O

O

OHOH

H2, Pd-C

Ni40 C, 2 atm.

NaBH4

H2

PtO2100C, 5 atm.


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HydrideReducingAgents

Lithium Aluminium Hydride (LiAlH4)

One of the most powerful reductants, Highly flammable

Sodium Borohydride (NaBH4)

Reduce aldehydes and ketones in the presence of esters,

reactions are carried out in protic solvents including H2O

RC

R'

O-

HRC

R'

OH+

RC

R'

O H

H

B+

H

HHH

B

H

HH

-

ReducingAgents

SodiumBorohydrideCerium(III)Chloride(Luche

O OH

NaBH4

(J.Am.Chem.Soc.,1981,103,54545459)

Chemoselectivereductionofaketoneinthepresenceofamoreelectrophilicaldehyde

O OH OH

+

97% 3%

NaBH4

CeCl3


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ReducingAgents

Sodium Cyanoborohydride (NaCNBH3)

milder than NaBH4 atpH7

atpH34:NaCNBH3 readily reduces aldehdyes andketones

: 3 r r m n m n = groups this property isresponsible forits most important use reductive amination:

HO N

CH3

H3C O

CO2EtNH2HN

N+ N

H

HN N

NCH3

H3C O

CO2EtNaCNBH4

EtO2C EtO2C

ReducingAgents

DIBALH,Diisobutylaluminiumhydride

verywidelyusedreducingagentespeciallyforreducingesters

esterscanbereducedtoeitherthealdehydeorthealcoholdependingonthestoichiometryandreactionconditions:


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ReducingAgents

DIBALH

,amides,isoneofthemostfrequentmeansofconvertingacarboxylicacidtoanaldehyde.

ThereactionofWeinrebamideswithorganomagnesiumcompoundsleadstoketonesinhighyields,

ReducingAgents

MeerweinPonndorfVerleyReductionwithAl(OiPr)3

thebyproductisacetone

thereactionisreversible thereverseoxidationis

knownastheOppenauerOxidation.


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ReducingAgents: Borane

BoraneBH3,isgasandunstabletobeisolated,butexistseitherasthedimerB2H6oraLewisacidLewisbasecomplexe.g.BH3 xTHForBH3 xMe2S

y ro ora on o enes

Mechanism:

ReducingAgents:Borane

Reduction of Carboxylic AcidsBorane is best reagent for selectively reducing carboxylic

acids to alcohols in the presence of esters

Reduction of Ketones and Enones

Reduction of Amides


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ReducingAgents

RaneyNickel

mostwidelyusedinthehydrogenolysisofCSbonds.

alsousedinthehydrogenationofalkenesandalkynes.

ro uce y rea ngn c e a um n uma oyw concentratedsodiumhydroxide

2Al + 2NaOH + 6H2O 2Na[Al(OH)4] + 3H2

ReducingAgents

Clemmensen Reduction

Aclassical method forcomplete reduction ofacarbonyl group (inketones andaldehydes).

Wolff-Kishner Reduction


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ReducingAgents

Hydrogenation with

Hydrogen and a H2 / PtCH3 H

Transition Meta Cata yst

Partial Reduction ofAlkynes

Lindlar's catalyst (Pd-

CH3 CH3

CH3H

a 3- s e moswidely used. The reaction is

stereospecific giving onlythe synaddition product

ReducingAgents

Hydrogenolysis Benzylether andbenzyloxycarbonyl protectinggroupsare

readilycleavedbyPd/C/H2 undermildandneutralconditions.


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ReducingAgents

Dissolving Metal Reductions (Sodium/Ammonia or Lithium/Ammonia) Regiospecific Enolate Formation

OH OLi OBr

BirchReduction:Partialreductionofaromaticrings

CH3

Li, NH3

1 eq H2OCH3 CH3

CH2

Na, NH3

EtOH

Reduction of Alkynes to (E)-

alkenes

ReducingAgents:Bu3SnHFreeRadicalReductions

with tributyltinhydride

(Bu3SnH)

AIBN undergoes thermal homolysis at 60 C to give nitrile-stabilized radicals that abstract the hydrogen atom from Bu

3

SnH.


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ReducingAgents:Bu3

SnHSynthesis of Corey lactone

Carboncarbon bond formation using radicals

Metathesis

The 2005 Nobel Prize in ChemistryYves Chauvin, Robert H. Grubbs, Richard R. Schrock

Mechanism

Example: Ring-Closing Metathesis Reaction for Synthesis of

Ru

NN

CH3

H3C

CH3

CH3

CH3

CH3

Cl

Cl

PCy3

Grubbs second-generation catalyst

Documents

3 Selected Reactions