carbon nucleophiles : organometallics of li, mg etc. 1. cyanide :well known 1 carbon unit 2....
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Carbon Nucleophiles : Organometallics of Li, Mg etc.
1. Cyanide : Well known 1 carbon unit
2. Acetylides : pKa = 25
HHNa
NaHR X
RH
Requires polar solvent to solubilize CN-
LiCN – THF NaCN – DMSOKCN – need 18-C-6
HREtMgBr
MgBrR
HRR'Li
LiR
3. Grignard Reagent : R-MgX
a. preparation
R X + Mgether
additivesR MgX
Additives : mechanical force, I2, MeI, BrCH2CH2Br to activate the surface of heterogeneous reaction.Reactive Mg ( Rieke Mg) : prepared from MgX2 + K --- black Mg powder
Reactivity of Halides : RI > RBr > RClradical intermediates through electron transferLoses stereochemistry !!
b. structure
2 RMgX R2Mg + MgX2
X
Mg
X
Mg RR
Solvent dependent, sometimes temp. dependent
3. Grignard Reagent : R-MgX
c. reaction
RMgX + R' X R' R
Usually not so good reaction except for MeI or BnIWith CuI or LiCuCl4 cat. Reaction works
Self condensation is called Wurtz coupling – problem during Grignard formation
RMgX +O OHR
RMgX +R R'
OR' CN
3. Grignard Reagent : R-MgX
c. reaction
Reduction of ketones
O MgBrOH
MgBrL O
S+
L OH
S
Very low e.e.
OH
MgL
S
4. Alkyl lithium
a. generation
+i) R X + 2Li R Li Li X
Usually contains Na(0.02%)Accelerates reaction
Cl : ppt.Br : solubleI : cannot formExcept MeI, ArI
ii) Metal-Halogen exchange rxn.
+Ar X + n-BuLi Ar Li n-Bu X
++ 2 t-BuLiBr Li + + LiBr
Sometimes faster than acid-base reaction
O O
C6H13 SPhLi-naphthalenide
O O
C6H13 Li
- 78oC O O
C6H13 Li
- 20oC
4. Alkyl lithium
a. generation
iii) Transmetallation – gives clean generation
+ 4 PhLiSn Li + Ph4Sn4
4
+ PhLi + Ph4SnSnPh3 Li
Too reactive to form by other ways
Too slow to form by other ways
iv) Metal-Hydrogen Exchange
EtLi + EtH +
Li
a. generation
iv) Metal-Hydrogen Exchange – directed metallation
+ BuLi
OMe OMe
Li O- inductive effect
+ BuLi
O NEt2 O NEt2
LiTMEDA
+ s-BuLiTMEDA
N
O Ot-Bu
N
O Ot-Bu
Li
through chelation
b. structure
Tetramer in Solid state
Me
Me Li
Li Me
Li
Li
In solution : monomer to hexamer depending on solvents, salts, additives
Reactivity : less aggregate, more reactive
c. reactions
Similar reactivity to Grignard for RX, carbonyls, nitriles
Often times act as base rather than nucleophile
Li
TMEDA
room temp. Li
Unusual reaction
JACS 1989, 111, 765
Cf. MgBr
MgBr
c. reactions
+ R'LiRCOOLiR R'
OLiOLi H2O
R R'
O
Quenching excess R’Li is important !
N
O
OMe
OMe
+ Li
O
OMe
N
O
OMe
OMe
Li
via
Weinreb amide
Asymmetric synthesis
+ MeLiH3C CHO
H NBn2
H3C
H NBn2
OH
H3C
H NBn2
OH
+
91 : 9
H
Bn2N
MeO
H
Me-Li Felkin-Anh Model : Chem. Rev. 1191 (’99)
S
L
MO
H
Nu:
+ BuMgBrC7H15
H OMOM
C7H15
H OMOM
HO
C7H15
H OMOM
HO
+
99 : 1O
BuBu
C7H15
H
OMOMO
H
BrMg-Bu Mg2+
Chelation control
Asymmetric synthesis
N
MeO
BnO
N
t-BuO
t-BuLiN
MeO
BnO
N
Ot-Bu
Li
N
O
O
Ph
O
PhMgBr
CuBr(cat.)N
O
O
Ph
OPh
98 : 2
A.I. Myers, Het. 295 (’89)
ArCH2BrN
MeO
BnO
N
t-BuO
CH2Ar
97% e.e.
JOC, 766 (’93)
MeMgBr
O
O
O
H
*RO
O
OH
H3C H
*RO
O
OH
H3C H
+
99.7 : 0.3CC, 988 (’82)
5. Organozinc (R2Zn) : d10, low reactivity: less nucleophilic, less basic
a. generation
R MgCl + ZnCl2 R2Zn + MgCl2
R X + Zn R2Zn + ZnCl2
b. reactions
Reformatsky reaction
+ ZnY
X
O
Y
OZn
O
Y
O
OH
R2Zn +
ONo Reaction
more selectivehigh functional group tolerance
lewis acid
R
OH
MgCl2TMSClBF3TiCl4
Synthesis, 571(’89)
b. reactions
R2Zn +
OR
OH
activator N N N OH N SH
activator
stereoselective addition to carbonyl with chiral activator
EtOOCBr Zn
EtOOCZnBr
functional group tolerability in the reagent
NMe2
OHNH
Ph
Ph
OH
NHTf
NHTf
Asymmetric reaction
NCHO
+ Et2Zn
OH
2 mol%
OH
99% e.e.
Noyori : ACIE 1991, 30,49
N
O Zn
R
Zn
R R
OH
R'
Model of catalyst – not real
Works well with aryl aldehydesWith alkyl aldehydes e.e. are not high
Asymmetric amplification : nonlinear effect
NCHO
+ Et2Zn
OH
8 mol%
OH
98% e.e.100% e.e.
95% e.e.15% e.e.
catalyst % e.e.
product% e.e.
Dimeric form of Cataylists are usuallyResponsible for the effect
Asymmetric amplification : nonlinear effect – mechanisms proposed
SS RR
S R
SR
+
Khomo
Khetero
catalytic
cycle
catalytic
cycle
Khetero > Khomo
Dimeric form of Cataylists are usually responsible for the effect
Noyori, Kitamura, JACS, 9800 (’98)
SS RR
SR
Kdimer
catalytic
cycle
catalytic
cycle
catalytic
cycle
Blackmond, JACS, 10103 (’01)
N
N
CHO
+ i-Pr2Zn N
N
OH
(20 mol%)
85% e.e.Ph
NHH
chiral initiator
C.P.L.racemic mixture
0.1% e.e.
Asymmetric auto catalyst : origin of chirality in nature (?)
N
N
CHO
+ i-Pr2Zn N
N
OH
(20 mol%)
N
N
OH
5% e.e. 39% e.e.
39% e.e. 76% e.e.76% e.e. 85% e.e.
85% e.e. 89% e.e.Nature 1995, 378, 767
JACS 1998,120, 12157ACIE 2000, 39, 1510
Homework
Chapter 7 : 1, 4, 5, 6, 8, 14
Due : May, 18