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Wittig-type Reactions - Larock p. 327-350 1,2-Disubstituted Olefins
Metathesis Reactions - Grubbs group Tri & Tetrasubstituted olefins (see other handout)
Elimination Reactions - Larock p. 251-315 Terminal Olefins (see other handout)
O
R'
R
RRR R
YX
R
R3P
R''
R'''
R'
R
RR
R
R'
R
R''
R'''R'
R
R
R
R
RR
R
R
R
R R
R
RR
reagent
+E Z
+Catalyst
Olefin Synthesis
-Plethora of references in the literature on olefin synthesis: see Larock 2nd ed. p. 215-562
-These can be catagorized by reaction type: -Or categorized by the olefinic product:
Chem 6352Jeremy May
Note: these are much more difficult because of E/Z issues!
IV
III
II
I
R R
H N N H
Cr
CO
CO
CO
HBR2
H
R R
BR2
RR
OMe
AcOH
CO2Me
OH
R R
H
R R
H
1,2-Disubstituted Olefins
•Z-olefins
Lindar's Catalyst, H2
Diimide reduction
, H2 (JOC 1985, 30, 1147)
Hydroboration/Acidic Quench
-From Acetylenes: by reduction
-From Rings:
O3, NaBH4
Pd/BaSO4, Quinoline (partially poisons catalyst)
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S+
-
O-
P
O
PhPh
Ph
H
HR
R'
Base: nBuLi, LDA, KHMDS, NaHMDS, LiHMDS, tBuOK, , etc.
(DMSO, NaH)
R X
R PPh3
PPh3
O
R'
H
H
Ph3P
RC HPh3P
R
OH
R
R PPh3
R PPh3 X
H H
R' H
O
C HPh3P
R
OH
R'
R H
HR'
R R'
Ph3P O
R PPh3
OH
R'
Ph3PH
R
-From Wittig Reaction:
preparation of ylide:
+Δ
Polar Solvent(THF, acetone, EtOH, MeCN)
pKa ~22
base
mechanism of the Wittig reaction: Chem. Rev. 1989, 863 JACS 1989, 6861 JACS 1981, 2823
Antiperiplanar
Kinetic Reaction Preference Betaine
Oxaphosphetaine
+
Vedejs
alkyl halide
R H
OLi
R H
O
Ph3P
Ar
H
I I
R H
O
Ph3P
H
I
PPh3
P
Ar
H
O
MeO
R H
O
R Ar
R Ar
R I
RAr
RAr
N
N
LiN
N
-Salt Effect:
Activation of the carbonyl by a Lewis acidic salt can increase the reaction rate and lower the selectivity. Also, it leads to a more open transition state (ie. there are fewer steric effects).
-To counter the effect:
Additives: HMPA, TMEDA → these break up and sequester lithium ions
Freeze/filter salts: becomes difficult preparatively.
-Examples: (Stork TL 1989, 30, 2173)
+ Very useful for Stille/Heck reactions.We will see this again later!
+ + base
-Phosphine effect: Synlett 1990, 605
+ +
Z E
Z form is slightly favored
+ +
Z E3
Z:E = 96:4
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I
OTHP
O
OH
THPO
o H
DMSONaH
Ph3PCO2H
1)
2) PhLi, then MeOH, -30 °C
R +PPh3PhLi R
PPh3R' H
O
+Li
-O
+PPh3
-Br
H HR R'
Ph-Li
+
+Li
-O
+PPh3
-Br
H R'R
OO
O O
PPh3
Br-
H+
(MeOH)
OO
O O
RR'
OTHP
HO
THPO
CO2H
+Li
-O
+PPh3
-Br
H R'R' H
The Schlosser Modification of the Wittig: reversal of selectivity for non-stabilized ylides.
1)
2) PhLi (-70 → -30 °C)3) MeOH or tBuOH (-30 °C)
warming (-30 °C)
W. S. Johnson, Progesterone Synth. JACS 1971, 93, 4332
97:3 trans:cis
-The Reaction of Lactols: (Corey, JACS 1969, 91, 5675)
ACIEE 1966, 5, 126Synth. 1971, 29Liebigs Ann. 1967, 708, 35
1) CuBr•DMS Et2O, -20 °C
2) E
R Li
R'' M
R H
H
H
R
R'
OH H
O
AlMe2
R
Me
R'' R
R'M
R H
HE
R'' R
R'E
I
R
MeI2
orE
-Carbometallation:
More Z-olefin formation:
E
-Copper/Magnesium:
+
+
E=I2, ,
There will be more examples with the trisubstituted olefin section.
-Zirconium/Aluminum:
Me3Al
Cp2ZrCl2
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BrH SiEt3
R H
Br
Br
SiEt3
H
R
H
Br
MeR
Br
SiEt3
HBr
RH
R'R
RI
Me2CuLi"Gilman Reagent"
BrR
BrR
Br2
Br2
H
R H
SiEt
Et3SiH
PtCl2
HR
-Hydrometallation/Halogenation:
TL 1981,22,315TL 1986,27,4351Org. Rxn. Vol. 41 (Lipschutz)
Hydrosilylation
Pd mediatedreactions
Further reaction of the vinyl bromide:
Note: treatment with I2 gives .
I
H BR'2
R H
I
H B
R HOH
R'R'
H H
R R'
I
B OHR'
HO
HO
H
R'
H
RI2
NaOHH
R H
BR'2
I2
H B
R HOH
R'
I
R'
R'2 BHR H
-Hydroboration/Alkyl transfer:
+
Note: One R' group will be wasted!
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n
R' R'R
n
N
Mo
CH3C(CF3)2OCH3C(CF3)2O
i-Pri-Pr
Ph
CH3CH3
Ru
PCy3
PhCl
Cl
NN
Ru
PCy3
PCy3
PhCl
Cl
X
RCM
X
X
ROMP
ROM
X
R
X
R1
R2
CMR1
R2
n
ADMET
- C2 H
4- C
2H
4
Diene Metathesis Reactions Terminal Olefin Intermolecular Reactions
- C2H4
•E-olefins: 1,2-disubstituted olefins continued
From Olefins: Olefin Metathesis
Schrock JACS 990, 112, 3875Grubbs Acc. Chem. Res. 2000, 34, 18
R1
R1
[M]R
R2
R2 R2
R1+
= Metal Alkylidene
[M]R
[M]R
[M]R
[M]
R1R1
R
R1
R [M]
R1 R2
R2 [M]
R2R1
R2
+
Typically a thermodynamic equilibrium process.The reaction produces a new carbon-carbon double bond.
-Mechanism of Olefin Metathesis:
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OH OH
NHO
S
O
O Me
NO
O
NH
H
Ar
CHO
Si(OR')3
B(OR')2
RSi(OR')3
H
H
RB(OR')2
H
H
RCHO
H
H
Macrocycle formation:Meyers ACIEE 2000, 9, 1664
Griseoviridin
O ClMg
RH
H
H
HO
RAr
H
H
HO
Examples:
Mixture of diastereomers
Cross Metathesis:Grubbs ACIEE 2002, 41, 3174
Ring closing for meduim reings: Furstner JOC 1996, 61, 8746
Dactylol
Substitutedstyrenes
Unsaturated aldehydes
Vinylsilanes
Vinylboronates
Ru
PCy3
PCy3
PhCl
Cl
Ru
PCy3
PhCl
Cl
NN
N
Mo
CH3C(CF3)2OCH3C(CF3)2O
i-Pri-Pr
Ph
CH3
CH3
Olefin Categorizing for Selective Cross Metathesis
Vinyl boronates
Terminal o lefin
Styrene
Styrenes (no large ortho substit.)
Styrenes (large or tho substit.)
Term inal ole fins, 1° a llylic a lcohols, esters
Allylboronate esters, A llylic halides
2° allyl ic a lcohols
Acrylate esters, amides, acids,
aldehydes, and vinylketones
Allyl phosphonates, phosphine oxides,
sul fides, protected am ines
Al lylboronate esters
Vinylsi loxanes
Per fluorinated a lkane o lefins
1,1-Disubstituted ole fins
Vinylphosphonates
Phenyl Vinyl Sulfone
4o a llylic carbons (a ll alkyl substituents)
3o a llylic alcohols (protected)
Type 1
Type 2
Type 3
Type 4
1,1-disubstituted ole fins
Disubsti t. α,β-unsaturated carbonyls
4o al lylic carbon conta ining o le fins
Perfluorinated alkane ole fins
3o al lylam ines (protected)
Trisubstitu ted a llylic alcohols (protected)
Olefin type
(fast
homodimerization)
(slow
homodimerization)
(no homodimerization)
(spectators to CM)
Acrylon itr ile
Terminal ole fins
Allylsi lanes
Styrene
Allylstannanes
1,1-disubstitu ted o lefins
1 2 3
Vinyl n itro o lefins
Tertiary a llylamines
Allylsilanes
1° a llylic alcohols, ethers, esters
Allylhalides
2o a llylic a lcohols
Unprotected 3° allylic alcohols
Vinyl epoxides
Vinyl d ioxo lanes
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AlO
RH
PhMe
HMPA-78 → -10 °C
O
H
CO2Me
From Aldehydes:
Wittig Reaction: Modifications to give E-selectivity
-Internal basic group promotes E-selectivity
Ph3P
O
+
R R
R
OH
Li, NH3(l) RR
H2O R OH
CO2Me
HO
From Acetylenes:
LAH
dioxane100 °C
JACS 1978, 100, 1942Corey Ch. 11 - Prostanoids Ch. 12 - Leukotrienes & EicosanoidsNicolaou ACIEE 1991, 30, 1100
Li
→
R'
R
Normally Kinetic
HPh3P
R'
R'
R
10% NaOH
H2O
1)BuLi
2)
100 °C
O H
R
Z-olefin
E-olefin
H
O
Ph3P
R'H
R
H
O
R'
Ph3PH
R
H CN
PPh3PPh3
O
ORH
Ph3P RBr
P R
O
Ph
Ph
PPh2Me
H R'
R' H
O
PPh2
H
RR'
PPh3
EWG H-Electron Withdrawing Group (EWG) on Wittig Reagent:
Consider the mechanism:
equilibration
Stabilization of this anionby EWG as R' will favor theultimate thermodynamicproduct.
Examples:
or
also: Phosphine oxides: S. Warren JCSPT1 1985, 2307 (Horner)
+
VedejsJOC 1984, 49, 210Synth. 1988, 911Corey and LazerwithJACS 1998, 12777
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P(OR)3
P CO2R
O
RORO
R
P CO2R
O
RORO
P CO2R
O
RORO P
O
RORO O
R H
O
P
O
H
R
H
CO2ROR
RO
OP CO2RO
RO OR
OR
H
H
P
O
RORO CH2
THF
-78 → 0 °C96%
P
O
RORO R
O
Br
M
, base
equilibrium
BrOR
O
RO R
O
O
OR
R
-Horner-Emmons-Wadsworth Modification
Arbuzov Rxn:
Phosphonate
HEW Rxn:
+
Also:
+
see Nicolaou amphotericin synthesis in Classics of Total Synthesis (many other examples).
R H
O
R H
O
O M
O
H
P ORO
RO
OR
R
H O M
O
H
P ORO
RO
OR
R
H
KHMDS18-crown-6
THF>95%
P
O
H
R
RO2C H
OOCH2CF3
OCH2CF3OR
OOM
R
PO
OCH2CF3
OCH2CF3
R
O
OR
OR
OOM
R
PO
OCH2CF3
OCH2CF3
P CO2MeF3CH2CO
O
POR
OO
RO
RO
M
-Still Modification of the HEW reaction: TL 1983, 24, 4405
2
Z-selective enoate synthesis
>50:1
irreversible, anda late transition state
fast
syn-aldol product
Transition state that leads to the syn-aldol stereochemistry.
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CHI3 (Iodoform)
CrCl2THF/dioxane
4:1
1) I2
2) CrCl2, Zn, DMF3)
R O
H
N
H
R
NH2
R
H
I
I
R'O
H
RI
CrCl2
RR'
-Takai Reaction:
many uses
>20:1 stereoselectivityNicolaou - Rapamycin Synthesis
Also:
95:5 E/Z
JACS 1986, 108, 6048JACS 1987, 109, 951
IH
CrII
CrII
proposed active intermediate
R
H
CrII
CrII
PhO2S Li
Me Me
OTBDPS
O O
Me
Me
H
Me
OTBSMeHMe
O
O
OH
R SO2Ph R
SO2Ph
R'
OHAc2O R
SO2Ph
R'
OAc
RR'
OAc
Na(Hg)
MeOH
O O
Me
Me
H
Me
OTBSMeHMe
O
O
Me Me
OTBDPS
RR'
RR'
OAc
-Julia Olefination:
BuLi
+e-
+e-
This elimation produces the thermodynamic product.
The reduction step is not stereospecific.
Phosphorus & Sulfur 1985, 24, 97JCSPK1 1978, 834Bull. Ch. Soc. Jpn. 1988, 61, 107
Evans: JACS 1990, 112, 5290Ionomycin Synthesis
1) add RCHO, -78 °C add AC2O, -78 °C to R.T.
2) Na(Hg), EtOAc/MeOH, -30 °C
70% yield86:14 olefin mixture
O
R'H
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Peterson:Ager:
JOC 1968, 33, 780Synth 1984, 384
O
OTMS
TMSO
Me
Me
O
O
Me
OTMS
1) KN(SiMe3)2, <50 °C
2)
3) H+, THF/H2O
O
N
N O
Me
SiMe3
(R1)3Si
H
R3R2
RLi
O
OTMS
TMSO
Me
Me
O
Me
OTMS
O
N
N O
Me
(R1)3Si
Li
R3R2
R5R4
O
R3
R2 R4
R5
(R1)3Si O
R3 R5
R2 R4
(R1)3Si OH
R3 R5
R2 R4
H2O
(R1)3Si
R3 R4
R2 R5
OH2
R3
R2 R5
R4
base acid
-Peterson Olefination:
Conditions control the stereospecificity of the elimination reaction, but the initial stereochemistry of the addition to the carbonyl must also be controlled to produce E or Z olefins specifically.
Tetrahedron 1994, 50, 6643
90% yield13:1 E:Z
For practice:What is the required stereochemistry for each step of the mechanism?
R
R'
OH
R
O
O
R'
R
O
OTMS
R'
O
OTMS
R'
R
H
TMSO R
R'
O
O
OTMS
R
R4
R3
R1
R2
O
TMSO
R4
R
H
R2
R1
R3
O
OTMS
R'
R
H
O
TMSO
R4
R
H
R2
R1
R3
H
TMSO R
R4
O R3
R2
Claisen Rearrangement: (more at the end)
Ireland-Claisen: very powerful reaction
Equatorial in TS!
LDA/TMSCl
trisubstitutedif R' ≠ H
trans olefin
Of Note:
Recall: Enolate geometry arguments•Esters + LDA → E-enolates•Esters + LDA + (HMPA or DMPU) → Z-enolates
Subst. at R1 → Z-enolateSubst. at R2 → E-enolate
Two new stereocentersand
trisubstituted olefin
H
H
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I
II
III
P
O
RO OEt
O
2
KOtBu, THFH
O
O
OTMS
R'
R
OEt
O
O
OTMS
R
R'
R''
R H
R'''
CO2Et
Trisubstituted Olefins
2,3 and 3,3 rearrangements (eg Wittig, Claisen, Cope, etc.)In fact 3,3 rearrangements are among the best methods.
Wittig Rxns: Typically not very selective (if R' and R'' are different).some examples with stabilized reagents: Kishi TL 1981, 37, 3873JACS 1979, 101, 259
From acetylenes by metalation reactions
+
R= MeiPr
CH2CF3
95 : 5 5 : 95 1 : 50
Still a serious stereochemical problem.
Acetylenes/Propargyllic alcohols
-With aluminum reagents:Corey:JACS 1967, 89, 4245JACS 1970, 92, 6314JACS 1968, 90, 5618
R
OH
1) LAH, NaOMe (1:2) Et2O or THF
2) I2
Reduces the Lewis acidityof any Al species.
Must be freshlyprepared!
OAl
R H
I
R
OH
R'2CuLi
R'
R
OH
R
OH
-If there is a small amount of Lewis acid present:
1) LAH, AlCl3 (60:1) 2) I2 H
R OH
I
R'2CuLi R OH
R'
Maybe ???
R
OAl
Cl Cl
ClHH
R
Al
O
Cl
Cl
→
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R H
OEtMgBrCuI
Et2O
E
E orMe3Al
Cp2ZrCl2CH2Cl2 or ClCH2CH2Cl
R H
O
E
Br
"EtCu"
E = H , I2, ,Et
R
Cu Et
R
E
R
R
Me
R
AlMe2Me
R
R
HO
ZrClCp
Cp Me
ClRR
ZrMe
Cp
Cp
R
ZrMe
Cp
Cp
R
ClZr
Cp
Cp MeZr
Cp
CpMe
Me2Al
Zr Cl
Cp
Cp
Me
R
Me2Al
-With organocopper reagents:
terminal acetylenes: Org. Synth. VII 236-240
Negishi Protocol: JOC 1980, 45, 2526JACS 1981, 103, 1276JACS 1981, 103, 4985
CatalyticProduct
I2Swartz's Reagent
ZrClCp
Cp H
LAH
Swartz's Reagent
RL MeH
RL Me
ZrCp
CpCl
RL Me
I
-Schwartz Hydrozirconation Reaction:Jeffrey Swartz (Princeton)
Cp2ZrCl2 Will not react with olefins!
TL 1987, 28, 3895TL 1990, 31, 7257
Hydroboration is not as selective between olefins and alkynes.
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Pd(0)
Bu3SnSnBu3
LiCl
RI
COPd(0)
1) LDA, Tf2NPh
2) Pd(0)
OO
Pd(0)
Et3SiHPd(0)
orBu3SnH
Pd(0)
COPhSnBu3
H
Me3Sn
OO
O
Me3Sn
OO
TfOOTIPS
OtBu
OTf
Bu3SnOTIPS
OtBu
OTf
Me3Sn
OO
Ph
O
OTIPS
OtBu
R
O
Enol Triflates: JOC 1986, 3405
McMurray TL 1980, 21, 4313
Also: JACS 1993, 115, 9293
NN
SO2ArLi
Li
LiN2
NN
-Also acyclic examples: TL 1997, 38, 8915TL 1997, 38, 8919
NN
SO2ArLi
Li
NN SO2Ar
Li
OMe
NN
SO2ArLi
Li
Ar
Ar
Li
Ar
I
warm- N2
- LiSO2Ar
OMe
BrnBuLi
(2 equiv)
N
HN SO2trisyl
OMe
S ArO
O
Li
warmN
HN S
O
O
Li E
Shapiro Reaction Ex: Pacquette JOC 1980, 45, 3017Also: Sorenson
nBuLi (2 equiv)
-78 °C
golden yellowsolution
E
•trisyl group: prevents o-lithiation and nucleophilic attack at S
Corey and Roberts
nBuLi
64% yield
golden yellowsolution
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-Z-enol Silyl Ethers: TL 1997, 38, 5771JACS 1996, 118, 8765
Li
R-X
Brook
RearrangementAr
O Si
BaI2
- I
1)
Et2O, -78 °C2) BaI23) R-X
Li
Ph
OSi
TBS
O
Li
Ph
TBSO Li
Ph
OTBS
BaI
OTBS
R
Tetrasubstituted Olefins
Corey
Acyl silane
PhOBn
NR
PhOBn
NR
PhO
NN
Ph
PhO
NR
O
O
Ph
R'R
RhLn
HHRh2(OAc)4
H2N N
Ph
OPh
O
O
Ph OBn
OPh
OBnPh
N2
1 70 1:0
2 81 1:0
3 63 1:0
69 1:04
R'
O
R
R'
NN
Ph
RR'
N
R
N
RR'
Substrate Product Yield Z:Eentry
Applications of Olefin Synthesis:The Bamford-Stevens Reaction
JACS 2002, 124, 12426
Results in the lab: Can this reaction be made more powerful?
1,2-Hydride
shift
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H
O
Ph
Rh2(OAc)4
R1
O R4
N
R2
R3
R5
NPh
Δ
O
NN
Ph
OR1
R5
R4
R3
R2
[O]
HO R2
R1 R3
R4 R5
H R2
O
R1 R3
R4 R5
Bamford-Stevens
Claisen
(iBu)2AlH
-15 °C
iodolactonization
O
I
O
Ph
Δ or
Me2AlCl-45 °C
Coupling of the Bamford-Stevens reaction to a Claisen Reaction
R1 = Ar, vinyl, or alkyl
Yields: 63-87%
de: 75-99%
Mono, Di, and Trisubstituted olefins are accesible
As seen previously, aldehydes offer access to many transformations:
α-allyloxysubstituent
BS Claisen
H
O Ph
O
Ph
H
BS Claisen
OH
Ph
NR
O
NR
O Ph
Ph
H
O
Bamford-Stevens/Claisen/Ene
Bamford-Stevens/Claisen/Cope
Ene
Cope
68 % yield>20:1 dr
68 % yieldone isomer for
both olefins
Coupling of the Bamford-Steves Claisen to the Cope and Ene Reactions: