olefin synthesis handout - may labmay.chem.uh.edu/teach-files/23 olefin synthesis handout.pdf ·...

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)

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

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

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!

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:

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

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

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.

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

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

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

→

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.

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

-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

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: