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Organolithiums - Preparation and ReactivityLithium-Halogen exchange is an equilibrium process, and the position of the equilibrium variesWith the stability of the carbanion intermediate:
RLi + R'X RX + R'Li
Li +I
Li
+ I
Stability: sp>sp2>sp3
Alkyl iodides are more reactive than bromides and chlorides are inert.
Li2 +I
Li+
I
tert-butyllithium tert-butyllithium
H ++ LiI
Br OEt
1.1 BuLi
Li OEt
JOC, 1978, 1595
Stereospecificity:
Br
1. 2t-BuLi
Br
2.
77%
TL, 1986, 4839
Organolithiums - Preparation and Reactivity
I 1. 2t-BuLi
2.PhCHO
OH
JOC, 1990, 5404
Note: lithium-halogen exchange is faster than the rate of proton transfer!
I + CH3OH2 eq. tBuLi
H
93%
TL, 1986, 1861
O
NOMe
OMe
MeO
MeO
I
2 eq. tBuLi
OMe
MeO
MeO
O64%
TL, 1992, 5431
Mechanism of lithium-halogen exchange: "ate" complexation
Li I+ I
Li+
BuI
Bu
JACS, 1985, 4101
Less reactive
Directed Ortho Metallation
Chem Rev. 1990, 879DMG
RLiDMG
Li
E+DMG
E
DMG's:
Ar
O
NR2 ArO
O
NR2
O
NAr
ArOCH3
Ar N Ar
O OCH3 Ar–CF3 Ar–Cl
RN
NRAr
OR
ORAr
Ar–O-
ArCH3O-
Relative Rates of directed metalation:
SO2NR2, CONR, CH2NR>OCH3>CF3, F, NR2
ArN(CH3)2
ArCH2N(CH3)2
ArSO2tBu
CONR> CONR2>O
N
> OCH3 > Cl
Protecting groups serving as DMG's
OR
ORAr
O
NAr
JOC, 1982, 34Tet, 1983, 1983
Cl
O N1. 3 eq. BuLi2. MeI
THF, -78°C
Cl
O N
CH3
Directed Ortho Metallation
1.sec-BuLi2. MeI
THF, -78°C
O
NEt2
MeO
O
NEt2
MeO
CH3
Lithiation occurs ortho to the better directing group:
Aldehydes can be transiently protected:
O
H
N N
Li
THF, -20°C
OLi
N
NMe2
1.n-BuLi
2. MeI
THF, -78°C
3. H3O+
JOC, 1988, 7175
O
H
CH3ClCl CH3
Cl
Metalation of vinyl ethers and heterocycles: JOC, 1984, 1078
OCH3
O OH H H NMe
H
Acyl Anion Equivalent:
OCH3
H
1. t-BuLi
O
2.
LiOOCH3
H3O+
HOO
JACS, 1974, 7125
1.sec-BuLiTMEDA, -78°C
2. warm to rt
Carbamate directing groups can rearrange upon warming:
O
O
O
O
NEt2
O
O
OH O
NEt2
1.sec-BuLiTMEDA, -78°C
2. PhCHO, -78°C
O
O
O
O
Et2N
Ph
OH
JACS, 1989, 4829
Directed Ortho Metallation
Organocuprates
ORMgXor RLi
HO R
1,2 addition
O
RMgXcat. Cu(I)
OM
R
O
R
1,4-addition
Stoichiometric organocuprates:
MeLi + CuIEt2O
MeCu + LiI
MeLi
Me––Cu––Me Li+
"ate" complex
Cuprates other than vinyl, phenyl, or methyl are subject to !-Hydridr elimination;must be handled at or below -40°C
Cu
H R
R'
R––Cu––H +
H R
Organocuprates
Ease of ligand transfer:
> Ph–– > Me > Et >>PhS, R2N, RC C
Dummy ligands; non-transferable
Order of reactivity of Substrates:
O
>O
OR
, N
O
Me2CuLi
O
Me
O
OMeMe2CuLi
BF3•OEt2
O OMe
Me
unreactive substrates will react if Lewis acids are added to activate the substratetoward nucleophilic addition
JACS, 1977, 8068
JACS, 1978, 3240
Regiospecific Enolate Trap
O
R2CuLi
TMSClTMSO
R
MeLi
LiO
R
JACS, 1974, 7114
Organocuprates
Addition to acetylenes:
R' CO2R
Me2CuLiR' CO2R
Me Cu
stable at -100°C
cis-addition
0°C R'
CO2RMe
Cu
isomerize
Alkenyl Coppers can be trapped:
R' CO2R
Me Cu
E+ R' CO2R
Me EH3O+, NBS
Leaving Group Displacement:
X
O
Me2CuLiX
OLi Me
Me
O
-X-
X= SPh, Cl, Br, OAc, but not :ORTL, 1973, 3817
JACS, 1969, 1851TL, 1974, 925
mechanism: cis addition, trans elimination, net retention of stereochemistry
Ketone Synthesis
O Cl (t-Bu)2CuLi O
no epimerization of axial carbonyl group
Organocuprates
Addition to terminal alkynes: synthesis of trans or trisubstituted alkenes
R' H
R'Cu R' H
Cu R'cis-addition
H+
R' H
H R'
E+
R' H
E R'Mechanism of cuprate 1,4 addition
Me2CuLi +O SET
Me2Cu• Li+ +
O• O-
radical anion intermediate - short-livedEvidence:
O
OTos
Me2CuLi
•O
OTos
O
H3O+
trap the radical anion intermediate
Possible mechanism
TL, 1975, 187
O
Li
O
Li(CuMe2)n
LiO
CuMe2Cu(III)
oxidativeaddition
reductive elimination
LiO
JACS, 1989, 8276TL 1985, 6015
Higher Order Cuprates: More reactive toward a range of substrates:
MeLi + CuCN ==> MeCu-CN Li+ (Only Me transferred. CN is a dummy ligand)
2RLi + CuCN ==> R2Cu(CN) Li2
OrganoZincsOrganozinc reagents are low reactive organometallics. Et2Zn doesn’t add to benzaldehydeat room temperature, but the addition of TMEDA (a diamine) promotes addition at RT
O
H + Et2Zn
5 mol% TMEDA OH
racemic
ordinarily in the presence of a diamine
ZnMe Me
180°
Zn
H3C
H3C
NR2
NR2
145°increase in Zn-C bond length (1.95Å to 1.98Å)and decrease in bond angle makes methyls more nucleophilic in the presence of the coordinating diamine
Noyori developed the first highly enantioselective addition to aldehydes utilizing the chiral amino alcohol(-)-DAIB as a catalyst
N(CH3)2
OH
-DAIB
R
O
H
+ R2'Zn2 mol% (-) DAIB
R
OH
R'
R R' % yield ee JACS, 1986, 6071
Ph Et 97 98Ph Me 59 91PhCH2CH2 Et 80 90C6H13 Et 81 61
An example of Ligand-AcceleratedCatalysis
Enantioselective addition of organozincs to aldehydes
No alkylation occure when the ratio of ligand to Et2Zn was 1:1. Catalyticquantities of ligand were required. Proposed transition state assembly:
N
O
Zn
R
Zn
O
R
H
PhR
TL, 1987, 5237JOC, 1987, 4142
a dimeric zinc species containing only one chiral ligand
dimeric zinc species with two chiral ligands are unreactive
Prep of the Zinc reagents:
2 MeLi + ZnBr2 Me2Zn + LiBra.
b. 1. Et2BH
2. Et2Zn
Zn
2
Ic. Et2Zn,
cat CuI
Zn
2
Zinc-iodine exchange
hydroboration/transmetallation
transmetallation JOC, 1992, 1956
JOC, 1996, 8229
JOC, 1996, 7473
Enantioselective addition of organozincs to aldehydes
O
H
NHTf
NHTf
Zn(pent)2
Ti(OiPr)4
20mol%
OH
88%, 98%ee
JACS, 1997, 9130
ArylZinc additions:
R
O
H
Ph2Zn
Et2Zn
10 mol% cat.R
OH
Fe N
O
OH
PhPh
cat
R % yield % ee
i-Pr 75 91
tBu 68 94
PhCH2 82 83
PhCH=CH 97 90
ACIEE, 2000, 3465
Prep of Alkenylzinc reagents: alkenyl and aryl ligands are transferred much faster than alkyl from zinctherefore, this allows the use of mixed alkyl alkenyl zinc species.
RHB(Cy)2 R
B(Cy)2
Et2ZnR
ZnEt
RCp2ZrHCl R
ZrCp2Cl
Me2ZnR
ZnMe
Enantioselective addition of organozincs to aldehydes
Alkenylzinc additions:
R
O
H 1-5 mol% (-)-DAIB R
OH
R R' % ee
Ph Bu 96
Et C6H13 86
C6H5 t-Bu 98
R'
ZnEt
R'
Helv. Chim. Acta, 1992, 170
TMS
I
1. t-BuLi, ZnBr2
2. NMe2H3C
OLiPh
3. ArCHO
TMS
OH
Ar
95% eeJACS, 2002, 773.
OHO
H HB(Cy)2
Et2Zn,
1mol% (+)-DAIBJACS 1993, 1593
Alkynylzinc Additions to aldehydes
Alkenylzinc additions:
R
O
H Zn(OTf)2, Et3N
cat.
R
OH
R R' yield % % ee
C5H11 Ph 90 97
i-Pr Ph 96 92
Ph CH2CH2Ph 67 89
R'
H R'NMe2H3C
OHPh
=cat.
in situ-generated
zinc acetylide; reaction can
be rendered catalytic
at elevated temperatures
using 20mol% Zn(OTf)2
JACS, 2000, 1806
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