C=C bond forming reactions 1. Elimination X=halogen, sulfonate, amminium, sulfonium : basic condition --- anti elimination X=OH : acidic condition ---

C=C bond forming reactions

1. Elimination

H

X

X=halogen, sulfonate, amminium, sulfonium : basic condition --- anti elimination

X=OH : acidic condition --- rearrangement occurs

OH

H+

1. Elimination

Cl

NaOEt

Cl

NaOEt

CH3

Cl

H

H HH

+

H

Cl

H

HH

H3C

2. Pyrolytic syn-elimination --- retro-ene reaction

H

OO

300 ㅇ C

H

O

S

S

100 ㅇ CChugaev reaction

H

NO

100 ㅇ C

2. Pyrolytic syn-elimination --- retro-ene reaction

H

SO

< 100 ㅇ C

H

SeO

Room Temp.

General procedure

R

OHArSeCN, PPh3

or ArSePhthaim., PPh3R

SeAr

R

mCPBA

orH2O2

orNaIO4

3. Fragmentation

MetalsO

X

fragmentation

OMHO

O

TMSO

I

O

OMe

TMSO O

OMe

OH

t-BuLi, ether

OBr

O

Mg OBrMg

O

예외

X O

H

base

B

O

Grob fragmentation : ACIE, 1969, 8, 535

HOTs

OH

H

OH

OTs

H

H

OH

t-BuOK

O

HOTs

OH

H

OTs

OHH

O

H

OH

t-BuOK

OTs

ONaOMe

OTs

O-

OMeMeOOC

4. Others

From Hydrazone

N

R

NHSO2Ar

NaOMeN

NSO2Ar

R

O

OH

OMe

OH

BnO

heat

R R

From Diol

O

O

OMe

O

BnO

Cl Cl

S

S

O OMe

BnO

NP

NPh

40oC

Corey, TL, 1982, 23, 1979

Bamford-Stevens rxn. JCS 1952, 4735

NaOMe; LDAN

NSO2Ar

R R R

Shapiro rxn. Org. Rxn. 1976, 23, 405

3. Wittig Reaction Chemistry of Ylides

X YRnYlide : X YRn

P CR3 S CR2 N CR2

X RPh3P +

Formation of phosphorous Ylides

Ph3P R

X-

Ph3P R

base

R

R'R'CHO

R= Alkyl : base = BuLi, LDA E.W. NaOH

3. Wittig Reaction

Stereoselectivity

with stabilized ylides --- trans major

Ph3P

+

R1

R2 CHO

Ph3P O-

R1 R2

Ph3P O-

R1 R2

R1 R2

R1

R2

with non-stabilized ylides --- cis major non-polar solvent, salt free condition (HMPA) destabilizing phosphorous

-- this is not exactly correct

PPh3i) NaN(TMS)2 PPh3

with non-stabilized ylides

MeOOCCHO

COOMe

80%, >98% cis

mechanism

P CR3

R1

R2

+ O CR3

R4

C CR3

R4

R1

R2

R3P O-

R3P OR2

R1

R4

R3

betain

R2

R1

R4

R3

[2+2]

PPh3

H3C H

O

R

Hcis olefin

Schlosser modification

Ph3P

+

R1

R2 CHO -70oC

R3P OH

R1

H

R2

R3P O-

R1

H

R2

PhLi, -30oC

R3P+ O-

H

H

R2

HCl

R1

R2

R1

trans:cis > 97:3

ACIE, 1966, 5, 126

For Hindered carbonyls

+ Ph3PKOt-Bu, HOt-Bu

toluene, reflux

O

H

O

+ Ph3PKOt-Amyl, HOt-Amyl

toluene, refluxModhephene

Conia procedure Alcohol ensures the equilibrium between ketone and enolate

Anion of ylide

Ph3PBuLi

Ph3P t-BuLiPh3P

Li

O

Ph3P=CHLi

87% Corey, TL, 1985, 26, 555

MeOOC PPh3 Na2CO3 MeOOC PPh3

with stabilized ylides

RCOOMe

RCHO

mechanism

R3P OH

MeOOC

H

R

MeOOC R

slow

R3P OH

MeOOC

H

R

R3P OMeOOC

H

H

R

R3P OMeOOC

H

H

R

MeOOC

fast

R

Effect of oxygenation and protic solvent

OOHC

MeO O

O Ph3PCOOEt

O

MeO O

O

EtOOC

+

O

MeO O

O

COOEt

DMF 86 : 14

CHCl3 40 : 60

CH3OH 8 : 92

Helv. 1979, 62, 2091

O

NBoc

CHO

Ph3P

O

NBoc

O

NBoc+

THF 6 : 94

THF-MeOH (1:1) 93 : 7

TL. 2004, 45, 3925

Conjugate addition

Ph3P

+

CHO

O- O

LDAPh3P COOEt Ph3P

O

+

ROH

O

CHO

O

PPh3

R

O

O

R

O

OPh3P

O

3.2 Wadsworth-Honer-Emmons reaction

Base (LDA)(EtO)2P W

O(EtO)2P W

O

Li

BuLi or NaHR-CHO

WR

W = CN, COOR, CHO, SO2Ph, C(O)R, Ph, vinyl not with Alkyl or H

R-CHO

WR

(EtO)2P

O-

O

Does not eliminate spontaneously !

E-selectivetrans

OH

(EtO)2PO

Water soluble !

Preparation of the reagent

P(OEt)3 + X (EtO)2P

O

RRArbuzov reaction :

(EtO)3P+Cl COOEt(EtO)2P COOEt

O

(EtO)2P

O

R

i) BuLi

ii) R'COOEt

R' O

(EtO)3P+Cl(EtO)2P

O

O

R

O

R

Perkow reaction

cis selective olefination

Ph-CHO(F3CH2CO)2P COOMe

O

MeOOC+

Ph

KN(TMS)2

18-C-6

W.C. Still, TL, 24, 4405(’83)

Z:E = 50:1

C7H15-CHO(PhO)2P COOEt

O

EtOOC+

C7H15

NaH

THF

JOC, 64, 8406 (’99)

Z:E = 9:1

Stereo-selective olefination : Horner-Wittig reaction

(Ph)2P R

O

BuLi, -78oC(Ph)2P R

O

Li

R'CHOP(Ph)2

R

O

R'

OH

major

R

NaHDMF

R'

P(Ph)2

R

O

R'

O

oxidation

P(Ph)2

R

O

R'

OH

NaBH4

RNaHDMF

R'

R’COOEt

Enantio-selective olefination

N

P

N O Li

+

O

NP

NO

HO

CH3

AcOH

Hannesian, TL, 33, 7659 (1992)

(MeO)2P

+

O

N

O

O

O

O

KHMDS

18-C-6

O

X

Masamune, TL, 37, 1077 (1996)

92 : 8

> 99 : 1

4. Peterson olefination

Ph3PTMSCl

Ph3P

TMS PhLi

Ph3P

TMS

Ph3P

Ph Ph

O

Ph

PhPh3PPh

Ph

TMS

O-

via

Gillman, JOC, 27, 3647(’62)

Peterson

MgClTMS +

Ph Ph

O

Ph

Ph

TMS

OH

Ph Ph

KH or NaH

JOC, 33, 780 (’68)

TMS R'

Li(Mg)

+ RCHO RCH=CHR'

base

R

R'

syn-elimination

KH

OOTBS

O

OR

OOTBS

OR

i) TMSCH2MgCl

ii) KH

TMS

OHR

R'

via

acid

R R'

anti-elimination

BF3.Et2O

and its diastereomer !

5. Julia coupling

PhO2S R'

Li(Mg)

+ RCHO R'R

SO2Ph

OH

R'R

Na-Hg

(MsCl)

trans major

2 ~ 3 step sequence !

+ RCHON

N N

N

PhO2S R'

KHMDSR'

R

N

SO2S R'

or

One step viaN

SO2S R'

R-ON-

S

O

O2S

R'

R

5. Julia coupling

PhO2S R'

Li(Mg)

+ RCHO R'R

SO2Ph

OH

R'R

Na-Hg

(MsCl)

trans major

R"OOC R'

Li(Mg)

+ RCHO R'R

R"OOC

OH

R'Rhydrolysis

HOOC

OH

R'R N

O

O

TL, 1545(1975)

6. Ramber-Backlund reaction

R SO2

R'

Cl

base

R SO2

R' R'R

O

OBn

BnO OBn

BnO

O2S Ph

KOH-Al2O3, CF2Br2

O2S ( )n

Cl

t-BuOK( )n

32 – 52 %JACS, 114, 7360(’92)

O

OBn

BnO OBn

BnO

Ph

94 %

7. McMurry Coupling

O+

O MetalPinacol coupling OHHO

MgSmI2

Mg-TMSCl

CHOTiCl3

Zn-Cu or K or Lior LAH

77%, E:Z = 7:3

McMurry, Chem. Rev. 89, 1513 (’89)

TiCl3O

MeO

OCHO

Zn-Ag

MeO

O

56%

TiCl3 LiAlH4

OEtOOC

OEt O

38%

TL. 24, 1885 (’83)

Ziegler, JOC, 47, 5229 (’82)

8. Neutral methylenation

a. Oshima-Lombardo reagent TiCl4-Zn-CH2I2 TL, 2417(’78)

TiCl4-Zn-CH2Br2

MeOOC

O

OH

O

OTHF

MeOOC

OH

O

O90%

JACS, 108, 7408 (’86)

TiCl4-Zn-TMEDA

THFPh COOMe + RCHBr2

Ph

OMe

R

E : Z = 8 : 92

JACS, 119, 1127 (’97)

b. Takai alkenylation

MeOOC

CHO

OAc OBn

CHI3, CrCl2

THF MeOOC

OAc OBn

I98 : 2

JACS, 115, 2268 (’93)

9. Transition metal chemistry : neutral olefination

a. Tebbe’s reagent

Cp2Ti

Cl

AlMe2 Cp2TiNeutral, reactiveUnstable, limited

R X

OTebbe's reagent

R X

X= H, R

Working through Metathesis

Ph OMe

OTebbe's reagent

Ph OMe81%

Ph N

OTebbe's reagent

Ph N80%

Ph O

O

Tebbe's reagent

96%

Ph O

Tebbe, JACS, 100, 3611, 1978

X= OR, SR, NR2Pine, Grubbs, JACS, 102, 3270, 1980

b.Petasis reagent

Cp2TiCp2TiCl2 +R Li

R

R

R' X

OPetasis reagent

R' X

R

R can be TMS

JACS, 112, 6392, (1990)

O

+ (Cp)2Ti

TMS

TMS

TMS

82%

TL, 36, 3619 (1995)

c. Olefin Metathesis Grubbs, Tet., 60, 7117, 2004

A B

C D

A B

C DMetathesis

A B

C D

A B

C D

Olefin Metathesis

WCl6+ JACS, 90, 4133, 1968

(PPh3)2Cl2(NO)2Mo

JACS, 92, 528, 1970

JACS, 108, 855, 1986

Ot-BuO

Cp2Ti=CH2

Ot-Bu

Ot-BuO

Cp2Ti

Ot-BuOCp2Ti

R

LnM=CHR'

RR +

Mo

O

O

NAr

Ph(F3C)2H3CC

(F3C)2H3CC

T, 55, 8141, 1999

Schrock cat.Reactive, unstable

RuPh

PCy3

PCy3

Cl

Cl

RuPh

PCy3

Cl

Cl

NNMes Mes

Grubbs 1st gen.cat./ 2nd gen.cat.Reactive, stable

mechanismR

LnM=CHR'

+R

LnM=CH2

+

R' R

R

LnM

R

LnM

R

MLn

R

R

N

O

Grubbs 1st gen.

N

O

89%

H2, Pd(OH)2

N

O

O

O

O

HO N

S

Ru

PCy3

PCy3

Cl

Cl

Ph

(10 mol%)

CH2Cl2, 0.001 MRT, 12 h

66%

O

O

HO

O

1213

N

S

Nicolaou, JACS. 1997, 119, 7960

R

MeO OMe

R

OMeMeO

R

MeO OMe

Grubbs 2nd. Gen.

Smith III, JACS. 2000, 122, 4985

Synthesis of Epoxides

a. Sulfur ylide chemistry

S + Me-I S

Sulfonium salt

SBase (LDA)

Sulfur Ylide

+ SPh CHOPh

OCorey, JACS, 87, 1353, 1965

Ph

-O

S

Ph

S

Ph

R LDA Ph

S

Ph

R

R' R'

S

O

SH

OBuLi

C. Johnson, JACS, 95, 7424, 1973

RCHO O

R

S

O

t-Bu

O

S

t-Bu

O

t-Bu

O

Thermodynamic

kinetic

Cyclopropanation with Sulfur ylide

S

O

O

S

O

O

81%

89%

Soft Nu

Hard Nu

O

S

Ph

Ph 75%

C. Johnson, JACS. 1973, 7424

Trost, JACS 1973, 962

JOC. 1989, 4222

O

Ph

20% ee

S

O

NMe260%

PhCHO, DMSO, 25 °C

O

Ph

0% ee

S

BF4PhCHO, n-BuLi

SMe

OMe

CHO

Cl

(1 equiv.)

Ph Br

(1 equiv.)

+

(0.5 equiv.)

KOH, CH3CN, rt, 36 h

50%

OPh

Cl

47% ee(2R, 3R)

Asymmetric Epoxidation with Sulfur ylide

O S97% e.e. Tet. Asym. 1996, 1783

Catalytic Asymmetric Epoxidation with Sulfur ylide

Aggarwal, Acc Che. Res. 37, 611 ('04)

SO

Me

90-94% ee, high de,

35-74% yield.

R2S—CHR'

R2S

R'

R

O

RCHO N2CHR'

N2Rh=CHR'

Rh2(OAc)4

Application

S

OMeO

OBF4

-

N CHO

EtP2, DCM, -78oCN

O

OMe

O

80%

89% (trans:cis = 7:3)

(> 99% ee for both isomers)

N

OMe

O

79% (> 99% ee)

CDP 840

CHO

MeON

NTs

Na

40oC, 36h

O

OMesulfide (0.25 eq.), PTC (0.1 eq.), MeCN,

50 %, 90 (93% ee):10 (70% ee)

O

OH

O

배임혁 , ACIE, 42, 3274 (’03)

배임혁 , Tet., 60, 9725 (’04)

Synthesis of Epoxides

b. Darzen Condensation

EtOOC Li R'R

OCl

+

EtOOC

Cl

R

R'O-

R'R

OCOOEt

Asymmetric Darzen Condensation

HPh

ONH

O

Ts

O

Cl

+i) TiCl4, (iPr)2NEt

ii) K2CO3

NH

O

Ts

OO

Ph

A. Ghosh, OL, 6, 2725 (’04)

Extension of the reaction

EtOOC Li

Cl

+

OCOOEt

O CHO

H+

heat

Org. Syn., Coll V 4, 459, (’63)

Homework

Chapter 2 : 4, 7, 14,

Due : May, 11