Advanced Organic
Chemistry
Part B: Reactions and Synthesis
4th Edition
Francis A. Carey and Richard J. Sundberg
Kluar Academic / Plenum Publishers
Chapter 1. Alkylation of Nucleophilic
Carbon Intermediates
• Introduction
C-C bond formation is the basis for the
construction of the molecular frame work of
organic molecules by synthesis.
One of fundamental processes for C-C bond
formation is a reaction between a
nucleophilic carbon and an electrophilic one.
Reaction of C-nucleophile (enolate ions, imine
anions, enamines) with alkylating agents
Crucial Factor for C-C bond
formation by SN2 reaction
• (1) the condition for generation of the carbon
nucleophile
• (2) the effect of the reaction conditions on
the structure and reactivity of the nucleophile
• (3) the regio- and stereoselectivity of the
alkylation reaction
• (4) the role of solvent, counterions, and other
components of the reaction media that can
influence the rate of competing reactions
1.1 Generation of Carbanions by
Deprotonation
• The rate of deprotonation and the
stability of the resulting carbanion are
enhanced by the presence of
substituent groups that can stabilize
negative charge.
• Several typical examples of proton
abstraction equilibria is shown in
scheme 1.1
• Favorable equilibrium between a carbon
acid and its carbanion will be
established if the base which is used
appears below the acid in the table 1.1
• An ordering of some important
substituents with respect to their ability
to stabilize carbanion can be
established.
NO2> COR>CN-CO2R>SOR>Ph-SR>H>R
Strong base, but it is sufficiently bulky so as to be relatively nonnucleophilic.
Lithium, sodium, potassium of hexamethyldisilazane, [(CH3)2Si]2NH
Aprotic solvent: ether, tetrahydrofurane (THF), dimethoxyethane (DME)
1.2 Regioselectivity and Stereoselectivity
in Enolate Formation
Ideal conditions for kinetic control of enolate formation are those in which
deprotonation is rapid, quantitative, and irreversible.
Lithium is better counterion than sodium or potassium for regioselective
generation of the kinetic enolate, since lithium maintains a tighter coordination
at oxygen and reduces the rate of proton exchange.
Aprotic solvents are essential because protic solvents permit
enolate equilibrium by reversible protonation-deprotonation,
which gives rise to the thermodynamically controlled enolate
composition. Excess ketone also catalyzesthe eqiulibriation
by proton exchange.
Conditions of kinetic control usually favor the less substituted
enolate.
At equilibrium, thermodynamic controlled conditions, the more
substituted enolate is usually the dominat species.
1.3 Other Means of Generating Enolates
Driving force: very strong Si-F bond energy (142 kcal/mol)
1.4 Alkylation of Enolates
SN2 Displacement
Primary halide, sulfonates, allyl benzyl > sec halide >> t-alkyl halide (only elimination)
The rate of cyclization: intramolecular cyclization for
w-haloalkyl malonate esters
3 : 4 : 5 : 6 = 650,000 : 1 : 6500 : 5
b-Ketoacid and malonic acid undergoes facile decarboxylation.
Therefore, ethyl acetoacetate and diethyl malonate are synthetic equivalents
of acetone and acetic acid.
Dilithium derivatives of acetoacetic acid is also a synthetic equivalent of
acetone enolate. Hydrolysis step is unnecessary, and decarboxylation can
be done directly.
Alkylation also can be carried out using silyl enol ethers by reaction with
fluoride ion such as tetraalkylammonium fluoride salts.
Little steric difference between two faces, upper and lower faces.
trans
cis
1/1 ratio of the prducts
Pseudoaxial conformation because of allylic strain
The upper face of the enolate presents three hydrogens in a 1,3-diaxial
relationship to the approaching electrophile. (lower face are equatorial)
Axial attack from the lower face leads directly to the chair conformation
of the product.
1,3-diaxial interation with the approaching electrophile.
A strong preference for alkylation to give the cis ring junction
According to molecular mechanicsm the minimum-energy conformation of
the enolate is a twist-boat conformation
Intramolecular ring-closure reaction
J is more favorable than K due to the ring strain
1.5 Generation and Alkylation of Dianions
Second deprotonation
Ref. Scheme 1.8
First deprotonation
1.6 Medium Effect in the Alkylation of Enolates
DMF and DMSO are effective in enhancing the reactivity of enolate anions,
polar aprotic solvent.
Polar aprotic solvents possess excellent metal-cation coordination ability,so
they can solvate and dissociates and other carbaions from ion pairs and
clusters.
Polar aprotic solvents are good cation solvators and poor anion solvators.
Polar protic solvents coordinate to both the metal cation and the enolate ion.
Water, alcohol, or ammonia
Polar protic solvents are less reactive than the same enolate in a polar
aprotic solvent such as DMSO.
Despite the somewhat reduced reactivity of aggregated enolates, THF and
DMF are the most commonly used solvents for the synthetic reactions
involving (kinetic) enolate alkylation.
Enolate can be enhanced by adding a reagent that can bind a alkali-metal
Cations: HMPA, tetramethylenediamine(TMEDA), crown ethers.
12-crown-4; Li, 18-crown-6; Na, K.
Mg2+ < Li+ < Na+ < K+ : reactivity order of enolate; the smaller, the harder
strongly bind to oxygen
1.7 Oxygen versus Carbon as the Site of
Alkylation
Enolate anions are ambient nucleophile.
O-alkylation, when the enolate is dissociated.
Leaving-group effects on the C- or O-alkylation: hard-soft-acid-base(HSAB)
Oxygen is harder than carbon.
Oxygen leaving group such as sulfonate and sulfate are harder: reacts at
the hard oxygen site of the enolate.
The amount of O-alkylation is amximized by use of an alkyl sulfate or alkyl
sulfonate in a polar aprotic solvent. And that of C-alkylation is maximized
by an alkyl halide in a less polar solvent such as THF or DME.
With 5-membered rings, colinearity cannot be achieved easily. The
transition state for O-alkylation involves an oxygen lone-pair orbital
and is less strained than the transition state for C-alkylation.
The kinetically preffered site for both protonation and alkylation is the a-carbon
The a carbon has a great negative charge compared with g carbon.
Strong preference for O-alkylation in Phenoxide ions because C-alkylation
disrupts aromatic conjugation
Phenoxides undergo O-alkylation in solvent such as DMSO, DMF,
ethers, and alcohols. However, in water and trifluoroethanol, extensive
C-alkylation occurs.
1.8 Alkylation of Aldehyde , Esters,
Amides, and Nitriles
Alkylation of aldehyde enolate is not very common because of facile
adol condensation by base. But rapid, quantitative formation of enolate
avoids this: KNH2 in NH3, KH in THF.
Alkylation of simple esters requires a strong base: weak base such as alkoxide
promotes condensation reaction. Strong base: LDA, hesamethyldisilylamide
(KHMDS). Ref. Scheme 1.9
Enolate of N-acyl oxazolidinones
Diastereomeric
Mixture: 95/5
Easily separated
Further
hydrolysis
or alcoholysis
Further
hydrolysis
or alcoholysis
Final product would be 99% enantiomeric purity.
Good chiral auxiliary
Analgestic substance
1.9 The Nitrogen Analogs of Enols and
Enolates-Enamines and Imine Anions
Imine is the nitrogen analog of ketone and aldehyde.
Removed by
azeotropic
distillation
For secondary amine, vinylamine or enamine is formed.
Strong dehydrating reagents to drive the reaction to completion: TiCl4 or
Triethoxysilane. N-Timethylsilyl derivative: strong affinity of silicone for
oxygen than nitrogen.
The b-carbon atom of an enamine is a nucleophilic site because of conjugation
With the nitrogen atom.
Alkylation of enamine
Pyrrolidine enamine
Preferred enamine
A serious nonbonded repulsion (A1,3 strain) destabilizes isomer 7.
Because of the predominance of the less substituted enamine, alkylation
occur primarily at the less substituted a carbon.
trans
Imine can be deprotonated at the carbon by strong base to give the
nitrogen analog of enolates: imine anions or metalloenamines.
Isoelectronic and structurally analogous to both enolaes and allyl anions and
can also be called azaallyl anions.
In toluene it exists as dimeric form, but at high THF concentration, the monomer
Is favored.
Just as enamines are more nucleophilic than enols, imine anions are more
nucleophilic than enolates and react efficiently with alkyl halides.
The nitrogen substituent R’ is syn to the double bond are the more stable.
more stable
Lithiated ketimines  room temperature: thermodynamic composition
is established. less substituted isomer: the most stable structure.
Table 1.3 entry 2 : a) chelation of the methoxy group with the lithium ion
b) The interaction of the lithium with the bromide
c) the steric effect of the benzyl group
O
+
OMe
OMe
N
N
N
NH2
proline
LDA
Hydrazone is hard to be hydrolyzed.
OMe
N
N
I
Li
N
N
Li
H
1) CH3I
2) H3O+
O
H
OMe
OMe
Hydrazones are more stable than alkylimines.
Kinetically deprotonated
Enantioselective synthesis of carboxylic acid
1.10 alkylation of Carbon Nucleophile by
Conjugate Addition (Michael reaction)
A catalytic amount of base is use: thermodynamic control of enolate formation
W
Electrophile
W
Nucleophile: amine, alkoxide, sulfide anions
Common nucleophile: b-ketoester, maolonate esters.
Fluoride ion is an effective catalyst for Michael additions involving acidic
carbon compounds: excess use of fluoride because of formation of [F-H-F-]
O
CO2CH3
HO
OLi
+
O
+
OCH3
CO2CH3
-78oC
88%
5%
25oC
7%
85%
Hindered Aluminum tris(2,6-diphenylphenoxide) is an effective promoter.
Ketone enolates react with enone to give 1,5-diketones.ref scheme 1.12
Quaternary carbon atom centers are easily generated. (kinetically controlled
enolate)
Z-enolate favors anti-adduct and E-enolate favors syn-adduct.
Chelated transition state
The stereoselectivity can be enhanced by addition of Ti(O-i-Pr)4.
Much larger Ti(O-i-Pr)4 group replaces Li+.
When the conjugate addition is carried out under kinetic conditions with
stoichiometric formation of the enolate, the adduct is also an enolate until
the reaction is quenched with a proton source. Tandem reaction is possible.
Tandem conjugate addition reaction is an efficient means of introducing both
a and b substituents at enones.
Trimethylsilyl enol ether can be used with TiCl4.
-78oC
CH3
N O
O O
Ti
"aci" tautomer
The initial adduct is trapped in cyclic form by trimethylsilylation.
Other Lewis acid
Lanthanide salts catalyze addition of a-nitroesters even
in aqueous solution.
Alcoholic solution of potassium or sodium cyanide
Triethylaluminum-hydrogen cyanide and diethylaluminum cyanide
More reactive
Aluminum reagent might act as a Lewis acid at the carbonyl center
With chiral oxazoline, 30-50% diastereomeric excess (d.e.) can be achieved.
The addition of enamines of cyclohexanones show a strong preference
for attack from the axial direction, because the pi-orbital of the enamine
is the site of nucleophilicity.