Post on 23-Jan-2021
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