C-C bond forming reactions Known C-C bond forming reactions
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Transcript of C-C bond forming reactions Known C-C bond forming reactions
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C-C bond forming reactions
Known C-C bond forming reactions(New C-C bond forming reactions in KJM3200)
Organometallic coupling C-C bond forming reactions
Protecting groups in organic synthesis
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Addition to carbonyl groups
O
R R'
aldehyde / ketone
C N
R R'
O CN H-CN HO CN
R R'+ CN
Cyanohydrin
Addition of HCN (or cyanide salts)Formation of cyanohydrins (McM 19.7)
HO CO2H
R R'
HO CH2NH2
R R'
O
R R'
aldehyde / ketone
R''
R R'
O
R''
H3O+
R R'
HO
R''Not in McM
add of alkyne anions
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O
R R'
aldehyde / ketone
R''-MgX
R R
XMgO R'' H3O+
R R
HO R'' Addition of Grignard reagents (McM 19.8)other organomet. reagents see, lab ex. 8)
Other Grignard addition reactions
R-MgX
O1) 2) H3O+
R
OH Add to epoxide, McC 18.8
R-MgX
(2 equivs)
1) R'CO2R'' 2) H3O+OH
R R'
R
Add to esters, McM 21.6
R-MgXR'-CN N
R R'
H3O+ O
R R'
Add to nitrile. McM, 20.9
R-MgX1) CO2 2) H3O+ O
R OHAdd to CO2, McM 20.6
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PPh Ph
Ph
H
CR X
RPPh Ph
Ph
CR
R
H Strong BaseBuLi
PPh Ph
Ph
CR
R
PPh Ph
Ph
CR R
R' R'
OO
R'
R'
R
R
PhPh Ph
PPh3
Ph3Ph3
O +
R'
R'
R
R
1 or 2 steps
Phophorus ylide
Wittig reaction, McM 19,12
See also lab ex 6
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Conjugate addition
C C
EWGNu-X
C C
EWG
NuX
Alkene Funktionalized "alkane"
EWG: -COR, -CN, -NO2 etc
Nucleophilic addition to alkenes(chapt. 23)
Conjugate add., 1,4-add., Michael add.
O
R'' R'
2 RLi + CuI
Li(RCuR) + LiI O
R'' R'
R
H
O
R'' R'
H
RConjugate add. oforganocupratesMcM 19.14Lab ex 8B
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Alkylation to C=O
(also for instance RR2CHCN)
O
RH
ketone
R'NH
R'
sec amine
R
NR' R'
R
NR' R'
R-X
R
NR' R'
R
HydrolO
RR
Alkylation of enaminesMcM 23.12lab ex 11
O
RH
ketone, aldehyde, ester
BaseO
R
O
R
R-XO
RR Alkylation of enolate
anionMcM 22.8
O O
pKa ca 9
N
O
OH3C
pKa ca 10
O
pKa ca 19
O
O
pKa ca 24
R CH3-CN
pKa ca 25
(new)
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R
O
H
H1) Base, 2) R'2CO
R
O
H
OH
R'R'
3) H+ R
O
R'
R'Aldol reaction / condensationMcM 23.3 - 23.7
O
OHR
1) Base 2)
O
OR
R'R
O
O O
RClaissen condensation McM 23.10
O
RH
Ketone, ester etcprecursor of stabilized enolate anion
1) Base 2)
O
R
electron def. alkene
O
R
O
RMichael add.McM 23.11
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Electrophilic aromatic substitution
R-X, Lewis acid
RFriedel Craft alkylation (McM 16.3)
RCOX, Lewis acidO
RFriedel Craft acylation (McM 16.4)
Red
R
Alkylation of alkynes
HR
Strong base
RR'-X
RR
McM 8.8-8.9
Reduction R
R'
R R'
R
R'
pKa ca 25
(alkene, pKa ca 44)(Alkane pKa ca 60)
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CycloadditionsXX
H H
X X
H H
Add of carbenes / carbenoids(McM 7.6)Cyclopropanes
Diels Alder (McM 14.5. 30)6-membered rings
O OSigmatrophic rearrangementsfor instance Claissen rearrangement(McM 30)
Rearrangements
(chapt. 30, in the end of this course)
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C-C Bond Formation - Organometallic Coupling Reactions(McM 10.9, Lab ex 10)
C + X C C C
No nu subst if C sp2 or spReagents often unstableDifficult to makeStrong bases
R HNaNH2
R
pKa ca 25
CH3IR CH3
Br
Na
R
H
H
CH
Br
Elimination
pKa ca 44
pKa ca 60
pKa NH3 35
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Grignard reagents and Organolithium reagents
Reacts with carbonylsStrong bases
RMgX or RLi does not react well with alkyl halides in substitutions
R-XMg
R-Mg-X
R: prim, sek, tert alkyl alkenyl aryl
NucleophileStrong base
O
R1 R2
R2R1
R OMgX
R-HBase
R
R-X2 Li
R--Li + LiX
R: prim, sek, tert alkyl alkenyl aryl
NucleophileStrong base
O
R1 R2
R2R1
R OLi
BuLi used a lot as strong base
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Organocuprates (McM 10.9)
2 R-Li + CuI R2Cu Li + LiI
2 R-MgX + CuI R2CuMgX + IMgX
Gilman reagentDialkylcuprate
Participate in substitution with alkylhalides (Cl, Br, I)
(R: alkyl, alkenyl, alkynyl, aryl)
R2Cu Li + R-X R-R
alkylhalide
+ RCu + LiX
less reactiveAlkylcopper(i)
Mech. see next slide
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R2Cu Li
IR
I
R'
R
R'
R Cu R+ CuR
+ CuRR Cu R
R'
Also reaction with alkenyl halides and arylhalides (sp2)Not SN1 or SN2
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Palladium catalyzed coupling reactions (Lab ex. 10)
R-X + R'-Metcat. Pd(0)-complex
R-R' + Met-X
-aryl halide-alkenyl halide-alkynyl halide
R': alkynyl, alkenyl, aryl, alkyl-Met; (-MgX), -ZnX, -SnR3,- -B(OR)2,
R’-Met:
R’ZnX - Negishi coupling
- Esp. good for R’ = alkyl, R’ZnX generated in situ
R’SnBu3 / R’SnMe3 - Stille coupling
-R’ (alkynyl) aryl, alkenyl, organotin comp. tox R’SnBu3 / R’SnMe3 stable
R’B(OH)2 / R’B(OR)2 - Suzuki coupling
- R’ (alkynyl) aryl, alkenyl, Green react. R’B(OH)2 / R’B(OR)2 relatively stable
react. requires base
R’MgX - Kumada coupling
Less reactive, often Ni-cat. (less stable than Pd-cat)
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General mechanism
Pd(II) + 4 L PdL4 [Pd(0)]
I
PdL
LI
PdL2
Pd(0)
2L
PdL
L
L: Ligand, often PPh3
Generation of active catalyst(PdL2)from commercially available Pd(II) orPdL4 = Pd(0)
Pd(II)Pd(II)
MetMet-I
Oksidative addition[Pd oxs from Pd(0) tto Pd(II)]
Transmetallation(Ph transfered from Met Pd Pdno red ox)
Reduktive eliminationPd redused back to Pd(0)C-C between aryls formed
Met: -ZnX, -B(OH)2, -SnR3 (-MgX)
Alkenyl or aryl halidesPd complex from aklyl halides unstable
Alkynyl, alkenyl, aryl, alkyl reacts (depending on the metal used)
N
N N
N
X
OCH3
O
Formed by Pd-cat coupling
Highly active against Mycobacterium tuberculosis
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The Suzuki reaction
I
Pd
L
L
I
PdL2
Pd(0)
Pd
L
L
Pd(II)
Pd(II)
B
Oksidative addition
Transmetallation
Reduktive elimination
OH
I
Pd
L
L
HO
(or other base)
OH
OH
OH
B OH
OH
OHMore reactive
B(OH)4
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Special cases - No preformed R’Met
Coupling on alkynes - Sonogashira coupling
Coupling on alkenes - Heck coupling(Somewhat diff. mech.)
Via R' Cu
R-X +cat. Pd(0)-complex
Base, CuXR' H R' R
R-X +cat. Pd(0)-complex
BaseR'
R'
R
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Why difficult to couple alkyl halides
X
PdL2
ox. addL Pd L
X
H
H
β-hydride elimination
L Pd L
H
X
Trans metallation
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Protecting groups (PG) in organic synthesis (McM 17.9)A
B
C
B
C
D
and / or
A
D
A
B
SolutionsA C C
B
A
PG
C
PG
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Examples
Protection of ROH (McM 17.9)
BrHO
Mg Mg-BrHO
acidic basic
XMgO
Me3SiClBase
BrO
Si MgMgBr
OSi
"E+" EO
Si
acidor F-selective
cleavage
EHO
even more stable (acid / base):
OSi
cleaved by fluoride
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Other ex. of ROH protecting groups (not mentioned in McM)
R OH
PhCH2X, Base
H2 / cat
R O
benzyl ether
R OHR O
R'
O
ester
R OH
H3O+
O
cat H+
O OR
THP-ether(Acetal)
esters also for prot. of acids
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Protection of aldehydes / ketones (McM 19.11)O
O
O LiAlH4
HO
OHNaBH4
O
O
OH
HO
O
???
O
O
O
LiAlH4
HO
O
HO OHcat. H+ O
O
OO
HO
OO
acetal
H3O+
•Two extra steps
•The protecting group curse