C=C bond forming reactions 1. Elimination X=halogen, sulfonate, amminium, sulfonium : basic...
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Transcript of C=C bond forming reactions 1. Elimination X=halogen, sulfonate, amminium, sulfonium : basic...
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