CsingC

C-C bond formation
One of the fundamental reactions in Organic chemistry
Involves reaction between a nucleophilic carbon and an electrophilic carbon
Generally,
1. Enolate anions,
2. Enamines,
3. Hydrazones,
4. Hetero-atom stabilized anions,
5. Organometalic reagents,
6. Michel addition,
7. Epoxide opening,
8. Sigmatropic rearrangement.
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

EnolateS
Carbanion:
By the removal of a proton from a carbon by a Bronsted base.
Enolate anion:
By the removal of a proton from a carbon alpha to a carbonyl group.
Condition:
Acidity of C-H bond greater than the acidity of conjugate acid of
the base used for deprotonation
pK a of C-H < pK a of BH
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Enolates
Formation of enolate depends
Acidity of C-H bond,
Base
The acidity of C-H bond depends on the functional group attached to it.
The order of acidity,
NO 2 > COR > CN > CO 2 R > SO 2 R > SOR > Ph ≈ SR > H > R
Base:
Non-nucleophilic base
ExampleS:
NH 2
- , Dimsyl anion, Ph3 P - are strong enough to convert ketone to enolate
LDA is a non-nucleophilic strong base
LiHMDS & NaHMDS
NaH, KH (Advantage: conjugate acid is H 2 )
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Regioselectivity
Predominant formation of one of possible two enolate anions
How to control ?
Experimental conditions
Kinetic control
Thermodynamic control
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Kinetic Control
Deprotonation of the most accessible proton
Why ?
Removal of less hindered proton is faster than the removal of more
hindered proton
Ideal contions
Ø Deprotonation is rapid, quantitative & irreversible
Ø Use very strong base: LDA, LiHMDS
Ø Aprotic solvent
Ø Absence of excess ketone
Ø Mostly lithium as the counter ion
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Favoured Conditions
Strong hindered (non-nucleophilic) base such as LDA
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Susceptible to substitution by base
Ester enolates
Use very hindered non nucleophilic base ( Li-isopropylcyclohexyl amide)
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Thermodynamic control
Reversible deprotonation give most stable enolate
Why ?
The stability of C=C bond increases with increasing substitution
Typical condition
Protic solvents allows reversible enolate formation
Example : RO - M + in ROH
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Determination of the composition
By trapping the enolate with an electrophile
CH 3 Li, THF
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Determination of the composition
CH 3 Li, THF
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Enolate anion preparation
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

From Enones
TMS Silyl enol ethers are labile, used as a trapping reagents.
From conjugate (1,4-) additions
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

From Halo Ketones
From reduction of α-halo carbonyls
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Enolate Formation
Major
Minor
Why A is major
A is fully conjugated, B is cross conjugated
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Enolate Formation
Ph 3 CLi / DME 28 72
Ph 3 CLi / excess ketone 94 6

Enolate Formation
LDA, DME 1 99
Et3N, DMF 78 22
LDA, THF 0 100
KH, THF 100 0
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Enolate Formation
13 87
In the presence
of excess ketone 84 16
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Alkylation of Enolates
The alkylation of relatively acidic substances such as β-diketones, β-
ketoesters can be carried out in alcohols as a solvent using metal
alkoxides as bases.
Reaction of the enolates with alkyl halides and epoxides
Or
Ø Primary halides & sulphonates, especially allylic & benzylic halides are
most reactive
Ø Secondery halides are react slowly
Ø Tertiary halides give only elimination products
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Alkylation of Enolates
Rate of alkylation increased in more polar solvents
Enolate alkylation: SN 2 , inversion of electrophile stereochemistry
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Alkylation of 4-t-butylcyclohexanone
Electrophile approaches from an “axial” trajectory- chair-like product
“Equatorial approach- higher energy twist-boat conformation
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Alkylation of Enolates
By taking sufficient base & alkylating agent equivalents, we can control
the mono & di-alkylation of methylene group
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Alkylation of α,β-unsaturated carbonyls
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Stork-Danheiser Enone Transposition
Overall γ-alkylation
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Chiral auxilaries
Evans Chiral Auxillaries
Chiral Enolates
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Chiral Enolates
Enantiospecific alkylations
Diastereoselectivity: 92-98%
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Aldol Reaction
Discovered independently by Charles-Adolphe Wurtz and Alexander
Porfyrevich Borodin in 1872
The reaction combines two carbonyl compounds
Forms a new β-hydroxy carbonyl compound.
These products are known as aldols, from the aldehyde + alcohol
β-hydroxy aldehyde
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Aldol Reaction
Counter ion varies the reactivity of the enolates
Reactivity Li + < Na + < K + < R 4 N +
Addition of crown ether increases the reactivity
An equilibrium reaction which can be driven to completion
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Aldol Reaction
In case of hindered enolates, the equilibrium favours reactants.
Mg +2 and Zn +2 counter ions will stabilize the intermediate β-alkoxycarbonyl
and push the equilibrium towards products
M = Li
M = MgBr
16% yield
93% yield
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Aldol Condensation
Dehydration of the intermediate β-alkoxy or β-hydroxy ketone can also
serve to drive the reaction to the right.
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

How to write syn & anti
Write your structure in a zig-zag manner
Syn
Anti
Put the substituents at the middle carbons
Depending on their relation, you can call them as syn, anti
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Stereoselective Aldol Reactions
+
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Steroselective Aldol Reactions
+
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Enolate Geometry
Enolate has two possible geometries
Enolate geometry plays an important role in stereo selection
Genarally Z-enolates usually give a higher degree of stereo selection than
E-enolates
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Zimmerman-Traxler Transition State
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Stereoselectivity
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Stereoselectivity
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Stereoselectivity
Li + , Mg +2 , Al +3 enolates give comparable levels of diastereoselectivity for
kinetic aldol reactions
Steric influences of enolate subtituents (R 1 & R 2 ) play a dominent role in
kinetic diastereoselection.
When R 1 is the dominent steric influence, then path A proceeds.
If R 2 is the dominent steric influence then path B proceeds
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Noyori Open Transition State Theory
Absence of a binding counterion
Non-chelation aldol reactions proceed via an open transition state to give
syn aldols regardless of enolate geometry.
Z-Enolates
Favored
Disfavored
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

E-Enolates
Favored
Disfavored
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

NMR Stereochemical Assignment
Coupling constants are measured as the average of various conformations
Syn Aldol
J AB = 2-6 Hz
Anti Aldol
J AB = 1-10 Hz
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Boron Enolates
Alkali & alkaline earth metal enolates tend to be aggregates- complicates
stereoselection models
B-O and B-C bonds are shorter and stronger(more covalent character)
than the corresponding Li-O and Li-C bonds- therefore tighter more
organized transition state.
Boron enolates are monomeric and homogeneous
Preparation :

Boron Enolates
Preparation :
Hooz reaction
J. Am. Chem. Soc. 1968, 90, 5936.
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Diastereoselective Aldol Condensation:
Boron Enolates
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Chiral Boron Enolates
1 : 33
(> 99% ee)
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Enolate Oxidation
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Synthesis of Chiral Amino Acids
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Oppolzer Camphor based auxillaries
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Asymmetric Acetate Aldol
Enolate Reaction
Chiral lithium amide bases
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Lewis acid Mediated alkylation of Silyl Enolates- SN 1 like alkylations
Alkylation with
3 o alkyl halide
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

First introduced by Gilbert stork
Enamines
monoalkylation
Gives product from kinetic enolization
cannot become coplannar
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Enamines
Chiral enamines
Imines- isoelectronic with ketones
ee 87-99%
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan
E= CH 3 , Et, Pr,
PhCH 2 , allyl

Isoelectronic with ketones
Hydrazones
More reactive than corresponding aldehyde and ketone enolate
Drawback: Can be difficult to hydrolyze
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Chiral Hydrazones
Asymmetric alkylations
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Chiral Hydrazones
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Aldol Condensation : Chiral Auxilaries
Li + enolates give poor selectivity (1:1)
Boron and tin enolates give much improved selectivity
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Mechanism
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Mukaiyama-Aldol Reaction
Silyl enol ethers as an enolate precursors.
Lewis acid promoted condensation of silyl ketene acetals (ester enolate
equiv.) with aldehydes
Proceeds through open transition state to give anti aldols (predominantly)
starting from either E- or Z- enolates
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Explanation
Not favoured
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Asymmetric Mukaiyama-Aldol Reaction
anti : syn =93 :7
E-enolate
R = Ph % de = 90 anti : syn = 91 : 19
n
Pr 85 94 : 6
i
Pr 85 98 : 2
Z-enolate
R = i Pr % de = 87 anti : syn = 97 : 7
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Mukaiyama-Jhonson Aldol Reaction
Lewis acid promoted condensation of silyl enol ethers with acetals
Fluoride promoted alkylation of silyl enol ethers
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Meyer’s Oxazolines
R= n Pr
C6H11
t
Bu
%ee (anti)=77 anti:syn=91:9
84 95:5
79 94:6
Anti-Aldols by Indirect Methods
Anti Aldol
product
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Anti-Aldols by Indirect Methods
Anti Aldol
Syn:anti
1:99
Syn:anti
97:3
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Syn Aldols by Indirect Methods
Michael Addition
Syn:anti=99:1
1,4-addition of an enolate to α-β-unsaturated carbonyl
1,5-dicarbonyl
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Conversions
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Conversions
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Addition to carbonyl compounds
Nucleophilic addition is a fundamental reaction of carbonyl compounds
Nucleophilic addition to a prochiral carbonyl group will give two
enantiomers
Addition of an achiral nucleophilic to a prochiral carbonyl group having
a chiral center will lead to two diastereomers
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Addition to carbonyl compounds
Addition of an chiral nucleophilic having a chiral center to a prochiral
carbonyl group having a chiral center, then it will lead to four possible
diastereomers
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Cram’s rule
When a keto group is attached to a chiral centre, then do the following
Look at size of the atoms or groups attached to adjacent carbon of the
ketone
Assign S, M, L for small, medium, large group respectively
Draw the Newman projection in such a way that it is flanked by the
small and medium groups
Then the nucleophile co-ordinates with the oxygen atom and attack
along the small group side
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Examples
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Felkin-Anh model
Cram’s rule doesn’t give quantitative assignment
Rules:
Keep the (R-C=O) perpendicular to the largest group or the most
electron-withdrawing group
Now the nucleophile will attach the carbonyl group near the small group
Nu -
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Chiral centre with an α-co-ordinating atom
If we have –OH, -SH, NH 2 or –OMe etc., attached to α-carbon then
Cram’s chelate model works
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Electronegative group on α-carbon
Keep the electronegative group opposite to carbonyl group to avoid the
dipole repulsion
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Prelog’s rule
Deals & predicts the formation of major isomer of addition of grignard
reagent to α-keto esters
Favored attack
Draw the a-keto ester as above
Keep the large group in the plane and also towards carbonyl side
Now the Grignard reagent will preferably attack from the side as small
group ‘S’
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan

Examples
CH-588: Organic Synthesis Course Slides. Instructor: Krishna P. Kaliappan