Download Carbon-Carbon Bond Forming Reactions

Carbon-Carbon Bond Forming Reactions
 Addition of Cyanide Nucleophiles
• SN2 displacement
R
X
KCN
NH2
R
R
R
CN
- X = I, Br, Cl, OTs, OMs
- SN2 process  reactivity? stereochemistry?
- one carbon chain extension
CHO
Me
R
O
• addition to aldehydes & ketones
O
R
KCN
R'
HCl (aq)
OH
R'
R
CN
- mechanism: nucleophile addition
- reversible process (KOH)
H3O+
Δ
OH
R'
R
CO2H
Carbon-Carbon Bond Forming Reactions
 Addition of Cyanide Nucleophiles
• SN2 displacement
R
X
KCN
NH2
R
R
R
CN
- X = I, Br, Cl, OTs, OMs
- SN2 process  reactivity? stereochemistry?
- one carbon chain extension
CHO
Me
R
O
• addition to aldehydes & ketones
O
R
KCN
R'
HCl (aq)
OH
R'
R
CN
- mechanism: nucleophile addition
- reversible process (KOH)
H3O+
Δ
OH
R'
R
CO2H
Carbon-Carbon Bond Forming Reactions
 Addition of Cyanide Nucleophiles
• SN2 displacement
R
X
KCN
NH2
R
R
R
CN
- X = I, Br, Cl, OTs, OMs
- SN2 process  reactivity? stereochemistry?
- one carbon chain extension
CHO
Me
R
O
• addition to aldehydes & ketones
O
R
KCN
R'
HCl (aq)
OH
R'
R
CN
- mechanism: nucleophile addition
- reversible process (KOH)
H3O+
Δ
OH
R'
R
CO2H
Carbon-Carbon Bond Forming Reactions
 Addition of Acetylide Anions
• SN2 displacement
R
X
R'
H
R
strong base
R'
- pKa alkyne ?
- deprotonation requires strong base: NaH, nBuLi, LDA, RMgX, NaNH2
- X = halogen or sulfonate
• addition to aldehydes & ketones
O
R
R'
R
H
strong base
OH
R
R
R'
- propargyl alcohols are useful synthetic intermediates
Carbon-Carbon Bond Forming Reactions
 Addition of Organometallic Reagents to Carbonyl Derivatives
• addition to aldehydes & ketones
O
OH
R'MgX or R'Li
R
R
R'
- Grignard and organolithium reagents are highly basic
- beware of acidic functionality (alcohols, carboxylic acids).
- beware of other reactive FG (including protecting groups)
• addition to esters
O
R
R'MgX or R'Li
OR
OH
R'
R
R'
- introduction of 2 equivalents of RMgX or RLi
- cannot stop at ketone stage except in special cases
Carbon-Carbon Bond Forming Reactions
 Addition Reactions of Cuprates
• epoxide opening
O
OH
R'MgX, CuI
or R'2CuLi
R
R'
R
- addition of nucleophile to least hindered position  mixtures can result
- SN2 mechanism
• addition to acid chlorides
O
R
O
R'2CuLi
Cl
R
R'
- chemoselective addition to acid chloride in the presence of ketones, enones, and
esters
- aldehydes may react
Carbon-Carbon Bond Forming Reactions
 Addition Reactions of Cuprates
• conjugate addition
O
R
O
R'2CuLi
R
R'
- regioselective 1,4-addition to enones and conjugated esters
Carbon-Carbon Bond Forming Reactions
 Alkylation of Enolates
• malonic ester & acetoacetic ester syntheses
O
O
MeO
O
R
O
1. base, R'X
2. H3O+, Δ
OMe
O
O
1. base, R'X
OMe
R'
HO
2. H3O+, Δ
R
R'
- dicarbonyl derivatives show enhanced acidity; lower reactivity
- pKa malonic ester (?) vs acetoacetic ester (?) vs ketone (?)
- deprotonate with weak base under thermodynamic conditions
RONa/ROH is typical; match base to ester
• addition to aldehydes & ketones
O
O
1. base
2. R'X
R'
- pKa ketone ?
- direct deprotonation requires strong, non-nucleophilic base, e.g. LDA
Carbon-Carbon Bond Forming Reactions
 Condensation Reactions of Enolates
• aldol reactions
OH O
O
R
NaOR
R
ROH
H
O
H
or
R
R
H
R
- symmetrical aldol: self condensation of aldehyde or ketones
- deprotonation with weak base under thermodynamic conditions:
NaOH, NaOMe, NaH
- can isolate aldol or elimination products
O
R
O
1. LDA (1.05 equiv)
2.
R
O
R'
OH
R'
R"
R"
- mixed aldol: reaction of two different aldehydes and/or ketones
- requires quantitative deprotonation of one carbonyl component (LDA)
- low temperature reaction  typically gives aldol product
Carbon-Carbon Bond Forming Reactions
 Condensation Reactions of Enolates
• Claisen condensation
O
O
R
R
OMe
MeOH
OMe
O
R
NaOMe
R
O
1. base
2.
R
O
MeO
O
O
R'
R'
- both symmetrical & mixed Claisen condensation reactions are known
- excellent method for preparation of beta ketoesters
- intramolecular Claisen known as a Dieckman condensation
Carbon-Carbon Bond Forming Reactions
 Friedel Crafts Reactions
• Friedel Crafts Alkylation
CR3
R3CCl
AlCl3
- electrophiles include halides, alcohols, olefins
- cationic intermediate  rearrangements of side chain possible
- overalkylation is possible
- deactivated benzenes and anilines do not react
- must consider regioselectivity when using substituted benzenes
directing effects: o/p or m (see handout)
• Friedel Crafts Acylation
O
O
Cl
R
R
AlCl3
- intermediate electrophile will not rearrange
- deactivated benzenes and anilines do not react
- over acylation does not occur
- consider directing effects as above
Carbon-Carbon Bond Forming Reactions
 Wittig Reaction
O
R
H
Ph3P=CHR'
H
H
R
R'
- reaction of aldehydes and ketones with phosphorous ylides
- excellent method for alkene synthesis
- reaction of aldehydes to give 1,2-disubstituted olefins is cis selective (some exceptions)
Carbon-Carbon Bond Forming Reactions
 Diels-Alder Reaction
CO2Me
Lewis acid
MeO2C
CO2Me
CO2Me
MeO
CO2Me
CO2Me
Δ or
Lewis acid
MeO
CO2Me
Me
Me
CO2Me
CO2Me
Me
CO2Me
Δ or
CO2Me
Δ or
Lewis acid
CO2Me
Me
- best case: diene electron rich; dienophile electron poor
- stereochemistry of both diene and dienophile is conserved
- endo TS is favored