1

SelectedSelected organicorganicreactionsreactions

Tapio NevalainenTapio NevalainenLääkeainesynteesit IILääkeainesynteesit II

20082008

Cross-coupling reactions

I

RR

R+

∆2 Cu2 + 2CuI

Ullman and Bielecki, Ber., 34, 2174 (1901)

Coupling reaction between aryl halides with copper (Ullmannreaction)

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, Sonogashirareactions.

2

Palladium-Catalyzed CouplingReactions

XR M R' R'R

XAr R' R'Ar

+ Pd0 catalyst

R, R' = aryl, vinyl X = Br, I, OTf

M = B Suzuki Sn Stille Si Hiyama Zn Negishi Mg Kumada

+ Pd0 catalyst

baseHeck reaction

Generalized mechanism for palladium-catalyzedcross coupling reactions

XR

M R'

R'R

R'

RPd

XM

X

RPd

LnPd0

Ln Ln

transmetalation

oxidativeaddition

reductiveelimination

M = B, Sn, Si, Zn, Mg

3

Mechanism of the Heck reaction

XAr

R

Hbase

X

HPd

X

ArPd

Ar

H

R

PdX

Ar

R

LnPd0

Ln Ln

oxidativeaddition

Ln

base

X

Palladium coupling Palladium coupling reactionsreactions:: Suzuki Suzuki CouplingCoupling

BOH

OH

R1

X

R2 R1

R2+

Pd-Catalyst

BaseN. Miyaura et al., TetrahedronLetters 1979, 3437; N. Miyaura, A. Suzuki, Chem.Commun. 1979, 866.

Example: SynthesisSynthesis of of losartanlosartan ((J. J. OrgOrg. . ChemChem. 1994,59, 8151. 1994,59, 8151--8156)8156)

PalladiumPalladium--catalysedcatalysed crosscross coupling coupling betweenbetween organoboronicorganoboronic acidacid and and halideshalides

NN

Cl OH

NNN

N

Tr

NN

Cl OHBr

NNN

N

Tr

BOH

OH+

trityl losartan

Pd(PPh3)4

AlkylsAlkyls, , alkenylsalkenyls and and alkynylsalkynyls cancan alsoalso bebe usedused as a as a reactionreaction partnerspartners . . PotassiumPotassiumtrifluoroboratestrifluoroborates and and organoboranesorganoboranes oror boronateboronate estersesters maymay bebe usedused in in placeplace of of boronicboronic acidsacids. . TriflatesTriflates (CF(CF33SOSO33

--)) maymay alsoalso bebe usedused as coupling as coupling partnerspartners.

4

HeckHeck reactionreaction

X

R1

R2

R1

R2+

Pd-Catalyst

Base

X = I or Br Pd-catalyst = Pd(OAc)2

Angew. Chem., Int. Ed. Engl. 1994, 33, 2379–2411.

Br

X

CH2

O

N O

O

Ph

O

N O

O

PhX

O

N O

O

PhX

CH2CH2

MgCl

J. Med. Chem., 48 (12), 3945 -3948, 2005

PPh3 Pd(OAc)2 Et3N

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

The palladium-catalyzed C-C coupling between aryl halides or vinylhalides and activated alkenes in the presence of a base

The use of an intermolecular Heck reaction in thecommercial synthesis of montelukast

(selective leukotriene receptor antagonist for the treatment of asthma)

NCl

S CH3

CH3

OHHOOC

NCl

OHCH2

O

O

I

CH3

NCl

OH

O

OCH3

PdH I

NCl

O

O

OCH3

Montelukast (Singulair)

+ Ln

Pd(OAc)2Et2N, MeCN, 85°C

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

5

StilleStille CouplingCoupling

RX

SnBu3

R'R

R'+[Pd]

Base+ XSnBu3

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, alkynyl X = Cl, Br, I , OAc, OSO2CF3

Ph2tBuO

CH3

SnMe3CO2Me

Br

CH3

CO2Me

CH3

Ph2tBuO

CH3

Pd(PPh3)4, tolreflux

J. Org. Chem., 1997, 62, 2535-2543

Example

C-C bond forming reaction between stannanes and halides orpseudohalides, with very few limitations on the R-groups

The The SonogashiraSonogashira--reactionreactionThe Sonogashira-reaction consists of the palladium-catalysed coupling of copper-acetylides and arylhalogenides to yield alkynylarenes (K.Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett.,1975, 4467-4470)

XCH R R+

Pd-catalyst

Cu(I)-salt

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

X

CH

CH3CH3OH

CH3

OHCH3

Y

CH

N

N

OMeNH2

NH2I

N

N

OMeNH2

NH2

YY

Y

N

N

OMeNH2

NH2

Y

+Ph3P, (Ph3P)2PdCl2,

CuI, Et3N

NaH, toluene,

heat

(Ph3P)2PdCl2, (Ph3P)3CuBr, Et3N, DMF

6

CrossCross--couplingcoupling reactionsreactionsNegishiNegishi CouplingCoupling

KumadaKumada CouplingCoupling

HiyamaHiyama CouplingCoupling

FukuyamaFukuyama CouplingCoupling

R1X

ZnXR2

R1R2+

[Kat]

E.-I.Negishi, J.Organometal.Chem. 653 (2002) 34

[Kat] = Ni(PPh3)4, Cl2Pd(PPh3)4 + 2(i-Bu)2AlHR1 = alkenyl, aryl, allyl, benzyl, propargylR2 = alkenyl,alkynyl, allyl, benzyl, aryl

R1X

MgXR2

R1R2+

[Kat] [Kat] = Pd(PPh3)4 or Ni(dppb)Cl2R1 = aryl, vinyl R2 = aryl, vinyl, alkylX = Cl > Br > I

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

R1X R'3Si R2 R1

R2+Pd cat

R'3Si = (RO)3Si, Me(3-n)FnSi F- or base

Y. Hatanaka, and T. Hiyama, J. Org. Chem., 1988, 53, 918, Y.

R

O

SR'' ZuIR'R

O

R'+

Pd cat

F- or baseTetrahedron Lett. 39 (1998), p. 3189

MitsunobuMitsunobu reactionreactionThe 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, 1-28. Hughes, D. L. Org. Reac. 1992, 42, 335-656.

R OH R Nu

O

O

N N

O

ONH

O

O

NH

O

O

P

OR

ROH

NuH

DEAD, PPh3

DEAD =NuH = R'CO2H, ArOH, RN3, RSH

, ,

7

MitsunobuMitsunobu reactionreaction: Mechanism: Mechanism

O

O

N N

O

O

PPh

PhPhP

+

PhPhPh

NO

O

N

O

O

P+

PhPhPh

NO

O

N

O

OH

OR

O

O

N NH

O

O

O R

P+

PhPhPh

HNuO

O

N NH

O

OH

O R

P+

PhPhPh

R NuO

P PhPhPh

OR

H

+ Nu-+ +

+

DEAD

The alkoxide ion attacks the positivelycharged phosphorus atom

The basic nitrogen anion removesa proton from the nucleophile

The phosphine adds to the weak N=N pii bond to give stabilized anion

The anion of the nucleophile attacks the phosphorus derivative of the alcohol in anormal SN2 reaction at carbon with the phosphine oxide as the leaving group.

MitsunobuMitsunobu reactionreactionInversion of Inversion of configurationconfiguration in the in the MitsunobuMitsunobu reactionreaction

OH OH

O

O

ODEAD, PPh3+

ExampleExample 1:1: SynthesisSynthesis of of MGLMGL--inhibitorinhibitor NN--ArachidonylArachidonyl MaleimideMaleimide

ON

OH

R1

OR2O

ON

R1

OR2O

I

CO2MeOHOH

CO2MeOHO

ON

R1

OR2O

OH(Bu)3Sn

Pd(dba)3, CuI, P(2-furyl)3, DMF, RT

DEAD, Ph3P, THF, RT

J. Med. Chem., 46 (20), 4232 -4235, 2003

ExampleExample 2: 2: ProteinProtein tyrosinetyrosine phosphatasephosphatase 1B 1B inhibitorsinhibitors

OHNH

O

O

N

O

O

DEAD, Ph3P, THF, -78°C

+

NAM

Saario et al. Chemistry & Biology, 12, 649-656, 2005

8

The The WittigWittig ReactionReaction ((Georg Georg WittigWittig, , Nobel Nobel PrizePrize in 1979)in 1979)

The The WittigWittig ReactionReaction allowsallows the the preparationpreparation of an of an alkenealkene byby the the reactionreaction of of an an aldehydealdehyde oror ketoneketone withwith the the ylideylide generatedgenerated fromfrom a a phosphoniumphosphonium saltsalt

WittigWittig reactionreaction goesgoes mainlymainly via the via the erythroerythro betainebetaine intermediateintermediate, , whichwhichleadsleads to the to the ZZ--alkenealkene

P+

H R'H

Ph PhPh

P+

H R'

Ph PhPh

P

H R'

Ph PhPh

RO

HP

+H

R'

Ph

PhPh

R'

R'PO

Ph PhPh

PH3P+

HR'H

OH R

P

HR'H

O RPh

PhPh

oxaphosphetane

Base _

_ + +_

erythro betaine

ylide phosphorane

O

OMe

PPh3CH3

O

OMeCH3

CH3

CH3

CH3CH3

OH+

J. Med. Chem. 1997, 40, 3626)

The The WittigWittig ReactionReaction

O

H P+

HPh

PhPh

O

OEt

O

OEt_+

YlidesYlides thatthat possesspossess substituentsubstituent groupsgroups thatthat cancan undergoundergoconjugationconjugation soso as to as to stabilisestabilise the the anionanion leadlead to the to the formationformation of of EE--alkenesalkenes..

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

R'

O

HP+

H R

Ph PhPh

R'RP

H R

Ph PhPh

O PPh3

R' R

O PPh3

R' R

1. PhLi, -30°C

2. HCl

BuLi, Et2O

-70 °C

KOtBu/tBuOH

Et2O

9

The The WittigWittig ReactionReaction:: The The WadsworthWadsworth--HornerHorner--EmmonsEmmons ReactionReaction

The The reactionreaction of of aldehydesaldehydes oror ketonesketones withwith stabilizedstabilized phosphorusphosphorus ylidesylides((phosphonatephosphonate carbanionscarbanions) ) leadsleads to to olefinsolefins withwith excellentexcellent EE--selectivityselectivity. .

PO O

OREtO

EtO PO O

OREtO

EtO

Li+

R'

O

HPO

OEtO

EtO Li+

O

ORR'BuLi +

NCH3

O

NCH3

O

OEt

OPO

EtO

EtO OEt

NaH, THF, 0°C

J. Med. Chem., 44 (23), 3937 -3945, 2001

Example: Example: SynthesisSynthesis of of tropanetropane--likelike analoguesanalogues

The The WittigWittig ReactionReactionSynthesis of Synthesis of prostaglandinesprostaglandines:: PGEPGE2 2 ja PGFja PGF22αα

O

O

OAc

O

H

O

OAc

O

O

P

OOMeMeO

O

O

OAc

O

OH

O

OH

O

OH

O

OO

O

O

O

O

OH

OTHP

O

OTHP

P

PhPh

Ph

CO2Na

OTHP

OH

OTHP

CO2-

OH

OH

OH

CO2HOH

O

OH

CO2HNa

+

OTHP OTHP

OH

OH

Corey aldehyde

+BuLi

Horner-Waldswoth-Emmons

Zn(BH4)2

1. resolution ofC15-epimers

2. K2CO3, MeOH TsOH

(i-Bu)2AlH

DMSO

AcOH

PGF2α

1. CrO3

2. AcOH, H2O

PGE2

Wittig

= THP

10

The The WittigWittig ReactionReaction: : SynthesisSynthesis of of acrivastineacrivastine ((antihistamineantihistamine))

N

N

HO2C

CH3

N

N

CH3

O

H

N

N

CH3

BrNP+

Ph

PhPh

N

O

CH3

Br

CH3

NCNBr Br

N O

HP

EtO2C

O

OEt

OEt

CH3

NBrNH

NBr Li

CH3

CN

Acrivastine

+

H3O+

t-BuOK

1. BuLi

2.

N,N-dimetyyli-formamidi

BuLi

Wittig

t-BuOK2. NaOH

1.

Horner-Wadsworth-Emmons

Julia Julia reactionreactionThe The additionaddition of a of a phenylsulfonylphenylsulfonyl carbanioncarbanion to an to an aldehydealdehydeoror ketoneketone leadsleads to to alcoholalcohol, , whichwhich is is esterifiedesterified in in situsitu. The . The reductivereductive eliminationelimination leadsleads to (to (EE))--alkenealkene..

SOO

Ph HR

RS

OO

Ph R

RLi

+ R'

O

R''

R'

R''

R

R

SOO

PhR

R

R' R''O Li

+

SOO

PhR

R

R' R''O

Ac

-Li

Ac2O

- LiOAcNa-Hg

- PhSO2-, - AcO-

CH3

CH3

Br

CH3

CH3

SO

O

PhCHOOH

OHCH3

CH3

SO2Ph

OPh

O

OHCH3

CH3

PhSO2Na

DMF

1, PhLi, -78°C2.

3. PhCOCl

Julia Olefination

Na/Hg

11

PetersonPeterson reactionreaction

PreparationPreparation of of alkenesalkenes fromfrom αα--silylcarbanionssilylcarbanions byby acidacidoror basebase--inducedinduced eliminationelimination..

SiR1

R1

R1 HR2

R

Li+ R'

O

R''

R'

R''

R

R2

Li+

SiR1

R1

R1 R

RSi

R1

R1

R1

R2

R

R' R''O

R'

R''

R2

R

-PhLi

- PhH

- (R1)3SiOLiBase

Acid- (R1)3SiOLi

SulfurSulfur containingcontaining reagentsreagentsThioacetalsThioacetals cancan act as act as effectiveeffective protectingprotecting groupsgroups and and cancan bebe reducedreduced bybyRaneyRaney NickelNickel to to affordafford the alkane.the alkane.

UmpolungUmpolung ((reversalreversal of of polaritypolarity): ): carbonyl group reacts as an electrophile carbonyl group reacts as an electrophile at carbon which polarity can be reversed when the carbonyl groupat carbon which polarity can be reversed when the carbonyl group is is converted into a thioacetal (dithiane). Acyl proton can be abstrconverted into a thioacetal (dithiane). Acyl proton can be abstracted by nacted by n--butyllithium to generate 2butyllithium to generate 2--lithiolithio--1,31,3--dithiane, which reacts as a nucleophile dithiane, which reacts as a nucleophile with alkyl halideswith alkyl halides. .

O

CO2Me

SH SH S

S

CO2MeCO2Me

RaNi/H2

BF3-Et2O

O

R H

SH SHS S

R H

SC

S

R

S S

R R'R R'

OHydrolysisBuLiHCl

R'-X

12

FluorinatedFluorinated pharmaceuticalspharmaceuticals

FluorinationFluorination agentsagents

N

NCH3

CH3

FF

NSF FF

OOCH3 CH3

CH3

CH3

NS

F

F

F

DFI2,2,-difluoro-1,3-dimethyl-imidazolidine

Deoxofluorbis(2-methoxyethyl) aminosulfur trifluoride

DAST diethylamino-sulphurtrifluoride

SiMe3

F

FF

FN

F FCH3

OCH3

OMe3Si

Ruppert-Prakashtrimethyl(trifluoro-methyl)silane Trifluoroacetamide

N+N

+ Cl

FS

NS

O O O O

F2BF4

-

Selectfluor1-chloromethyl-4-fluoro-diazoniabicyclo [2.2.2]octanebis(tetrafluoroborate)

NFSN-fluorobenzene-sulfonimide

Nucleophilic agents

Electrophilic agents Reagents to introduce CF3 groups

13

FluorinationFluorination agentsagents

AcO

AcOOAc

O

OAcAcO

OAcO

OAc

FO

Selectfluor

Prednisoloneenolacetate

R'

R OH

R'

R F

CH3

CH3

NS

F

F

F

CH3

CH3

NS

O

F+ +

DAST

H

O NSF FF

OOCH3 CH3

H

F F

CH2Cl2, reflux, 18 h

R R'

OSiMe3

F

FF

R R'

OSiMe3CF3

F-

OxidationOxidation ChemistryChemistryThe The SwernSwern OxidationOxidation

R'

R OHS

CH3

OCH3

Cl

O O

Cl

R'

R O

2. NR3

+1.

Mechanism Mechanism

Cl O

OCl

R'

R O

S+

CH3 O

CH3Cl O

OS

+

CH3Cl

CH3

Cl

R'

R OH

R'

R OS

+ CH3

CH3

S+

CH3

Cl CH3 R'

RO

S+ CH2

CH3

HS

CH3

CH3

SCH3

CH3O + CO2 + CO + Cl -

+ base- HCl

- H++

chlorosulfonium ion sulfonium salt sulfur ylide

14

OxidationOxidation ChemistryChemistryCoreyCorey--KimKim OxidationOxidation

allowallow oxidationoxidation aboveabove ––25 ºC25 ºC

R'

R OHS

CH3

CH3

R'

R O

N

O

O

Cl

2. NR3

1.+

The BaeyerThe Baeyer--Villiger Oxidation Villiger Oxidation

CH3

O

CH3

H2O2 CH3O

O

CH3BF3, ether

OxidationOxidation ChemistryChemistryDessDess--Martin Martin OxidationOxidation:: The The DessDess--Martin Martin PeriodinanePeriodinane (DMP), (DMP),

offersoffers selectiveselective and very and very mildmild oxidationoxidation of of alcoholsalcohols to to aldehydesaldehydes oror ketonesketones..

R'

R OH

R'

R OO

I

O

AcO OAcOAc

OI

O

OAc

+ 2 AcOH+ +

OppenauerOppenauer OxidationOxidation

R'

R OH

R'

R O

CH3CH3

O

CH3CH3

OHAl(i-PrO)3+ +

15

OxidationOxidation ChemistryChemistryOxoneOxone®® = = potassiumpotassiummonopersulfatemonopersulfate (KHSO(KHSO55) )

NefNef ReactionReaction: The : The conversionconversionof nitro of nitro compoundscompounds into into carbonylscarbonyls

R

O

RR

CH2

R

KHSO5

RCO2HR3N+-O-

(RO)3BR3P=O

R3PR3B

R3NRCHO

RCO2Me

RCH(OMe)2

RSO2R

RCO2H

RSR

R

NO2

R' R

O

R'

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

1. NaHPO4, MeOH

2. Oxone (0,7M H2O)

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

ReducingReducing AgentsAgents

Hydride Reducing AgentsLithium Aluminium Hydride (LiAlH4): One of the most powerfulreductants, Highly flammableSodium Borohydride (NaBH4): reduce aldehydes and ketones in the presence of esters, reactions are carried out in protic solvents including H2O

O

OH O

OHOH

NaBH4H2, Pd-C

Ni40 °C, 2 atm.

PtO2100°C, 5 atm.

SelectiveHydrogenations

16

ReducingReducing AgentsAgentsSodium Borohydride-Cerium(III) Chloride(J. Am. Chem. Soc., 1981, 103, 5454-5459)

Chemoselective reduction of a ketone in the presence of a more electrophilic aldehyde

O OH

O OH OH

NaBH4

NaBH4

CeCl3+

97% 3%

O

CHO

O

OMe

OH

CHO

O

OMeNaBH4

CeCl3

J. Org. Chem., 1979, 44, 4187-4189.

ReducingReducing AgentsAgentsSodium Cyanoborohydride (NaCNBH3)

milder than NaBH4 at pH 7at pH 3-4: NaCNBH3 readily reduces aldehdyes and ketonesat pH 6-7: NaCNBH3 readily reduces iminium ions but NOT C=O groups -this property is responsible for its most important use - REDUCTIVE AMINATION:

HR

O

HR

N+R' R''

HR

NR' R''

NH

R' R'' HNaCNBH4

MeCNpH 6

+

H

O NCH3

CH3 O

EtO2C CO2EtNH2

NHN

NH

NHN

NCH3

CH3 O

EtO2C CO2EtNaCNBH4 +

17

ReducingReducing AgentsAgentsDIBALDIBAL--H, H, DiisobutylaluminiumDiisobutylaluminium hydridehydride

very widely used reducing agent especiallyfor reducing estersesters can be reduced to either the aldehydeor the alcohol depending on the stoichiometry and reaction conditions:

AlH

CH3

CH3

CH3

CH3

DIBAL-H

R OR'

O

R H

O

R OH2 eq DIBAL-H

1 eq DIBAL-H

-78°C, toluene

Nitriles are also reduced to aldehydes

R H

NAliPr2

R H

O

R

N 1 eq DIBAL-H H+

ReducingReducing AgentsAgentsDIBALDIBAL--H H

Reduction of N-methoxy-N-methyl amides, Weinrebamides, is one of the most frequent means of converting a carboxylic acid to an aldehyde. The reaction of Weinreb amides with organo-magnesiumcompounds leads to ketones in high yields,

ClR

ON

CH3

OMe

O

RNH2

+

CH3

OMe

R'

O

R

ClH

O

R - 2 HCl

base+

Weinrebamide

1. R'MgX

2. H2O / H+

DIBAL-H

18

ReducingReducing AgentsAgentsMeerwein-Ponndorf-Verley Reduction with Al(OiPr)3

isopropanol behaves as the hydride donorthe by-product is acetonethe reaction is reversible - the reverse oxidation is knownas the Oppenauer Oxidation.

R R'

O

R R'

OH

HR R'

OAl

OiPriPrO

O

CH3 CH3

H

Al(OiPr)3

ReducingReducing Agents:Agents: BoraneBoraneBorane BH3, is gas and unstable to be isolated, but exists either as the dimer B2H6 or a Lewis acid-Lewis base complex e.g. BH3 x THF orBH3 x Me2S

Hydroboration of AlkenesCH2CH3

CH3

CH3

CH3

BH2

CH3

CH3

OHBH3 H2O2

BH2H

CH2CCH3

CH3CH2C

CH3

CH3

BH2H

OH O

CH2CCH3

CH3

BH2H

OH

O

CH2CH

CH3

BH

CH3

CH2

CH

CH3

CH3

O BH2 CH2

CH

CH3

CH3

OBH2-

OH

OH-

CH2

CH

CH3

CH3

OH

Mechanism:

19

ReducingReducing Agents:Agents: BoraneBorane

O OHBH3

. THF

- 50 °C

O

OH

EtO

O

OHEtO

OBH3. THF

- 10 °C

Reduction of Carboxylic AcidsBorane is best reagent for selectively reducing carboxylicacids to alcohols in the presence of esters

Reduction of Ketones and Enones

Reduction of Amides

OH NHNH

ONH2

BOC

OH NHNH

NH2

BOC

BH3. THF

0-23 °C

ReducingReducing AgentsAgentsRaney-Nickel

most widely used in the hydrogenolysis of C-S bonds.also used in the hydrogenation of alkenes and alkynes.

S SO CH3

OBn

O CH3

OBn

O CH3

OBn

O

SHSH

Raney nickel

EtOH, 40°C, 3h

J. Org. Chem., 1998, 63, 2058-2059

BF3

20

ReducingReducing AgentsAgentsClemmensen Reduction

A classical method for complete reduction of a carbonylgroup (in ketones and aldehydes).

R'R

O

R'R

H H Zn (Hg)

HCl, ∆

Wolff-Kishner Reduction

R'R

O

R'R

NNH2

R'R

H H H2NNH2

- H2O

KOH

- N2

ReducingReducing AgentsAgentsHydrogenation withHydrogen and a Transition MetalCatalyst CH3

CH3

CH3

CH3

H

H H2 / Pt

Partial Reduction of Alkynes

Lindlar's catalyst (Pd-CaCO3-PbO) is the most widely used.The reaction is stereospecific givingonly the syn additionproduct

R

R'

R

R'H

H H2

Lindlar'scatalyst

21

ReducingReducing AgentsAgentsHydrogenolysis

Benzyl ether and benzyloxycarbonyl protecting groups arereadily cleaved by Pd/C/H2 under mild and neutral conditions.

OROHR CH3

OO

NH

RNH2R CH3

H2

Pd / C+

H2

Pd / C+ CO2 +

ReducingReducing AgentsAgents

Birch Reduction: Partialreduction of aromatic rings

Na, NH3

EtOH

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

OH

CH3

OLi

CH3

O

CH3

CH2CH2

BrLi, NH3

1 eq H2O

Reduction of Alkynes to (E)-alkenes

R

R'

R

HH

R' Na / NH3

22

ReducingReducing AgentsAgents: Bu: Bu33SnHSnHFree Radical Reductionswith tributyltin hydride(Bu3SnH) R

XR

HBu3SnH

AlBN

NN

CH3

CH3

CN CH3

CH3

CNNH

NHCH3

CH3

CNCH3

CH3

NC

CH3

CH3

CNSnBu3H Sn Bu3CH3

CH3

CNH

Sn Bu3 R SnBu3X

AIBN2, 2'-azobisisobutyronitrile

+ +..

. +

+R-X +

60°C

– AIBN undergoes thermal homolysis at 60 °C to givenitrile-stabilized radicals that abstract the hydrogenatom from Bu3SnH.

ReducingReducing AgentsAgents: Bu: Bu33SnHSnH

O

O

OAc

OO

O

OAc

O

I

OH

O

OAc

OO

O

OH

OH

O

OAcI+

O

OH

(n-Bu)3SnH BBr3

Corey lactone

AlBN

KIH2O

I CNCH2 CN

Bu3SnH

AIBN+

Carbon–carbon bond formation using radicals

O O

ClEtO OEt

O O

EtO OEt

CH2 O CH3

O O

EtO OEtO CH3

Bu3SnH

AIBN .

Synthesis of Corey lactone

23

MetathesisMetathesis

CH2

OOH

OO

CH3

CH2

OOH

O

OCH3 CH2

OOH

O

OCH3

4-bromobutene, LDA, LiI

DMPU/THF, 1:1, -85 °C

Grubbs' catalyst C46H65Cl2N2PRu,

DCM, 40 °C

J. Med. Chem., 46 (7), 1165 -1179, 2003

R' CH2CH2 R'' R'

R'' CH2 CH2+ +catalyst

Ru

NN

CH3

CH3

CH3

CH3

CH3

CH3

ClCl

PCy3

Grubbs second- generation catalyst

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

R' R'

M

R'

R' R'

MR'

R'

M

R'

R'Ln Ln

Ln

Mechanism

Example: Ring-Closing Metathesis Reaction for Synthesis of Cyclopentenedicarboxylic Acid