2. Reaction of Carbon Nucleophile with Carbonyl Group

Introduction: aldol and Claisen condensation, Robinson annulation Wittig reaction, and related olefination methods

2.1 Aldol Addition and Condensation Reactions2.1.1. The General Mechanism

Prototypical aldol addition reaction is the acid- or base-catalyzeddimerization of ketone and aldehyde,

The equilibrium constant for the dehydration phase is usually favorable, because of the conjugated -unsaturated carbonyl system that is formed.

2.1.2 Mixed Aldol condensation with Aromatic Aldehyde

One of the most general mixed aldol condensation inovolves the use ofaromatic aldehyde with alkyl ketones or aldehyde.

Non-enolizable

Claisen-Schmidt Condensation

Pronounced preference for the formation of a trans double bond in theClaisen-Schmidt condensation of methyl ketones.

Base-catalyzed dehydration is slow relative to the reverse of the additionphase for the branched-chain isomer.

In base, the straight-chain ketol is the only intermediate which is dehydrated.The branched chain ketol reverts to starting material. Under acid condition, bothintermediates are dehydrated, however, the branched-chain ketol is formed mostrapidly, because of the preference for acid-catalyzed enolization to give themore substituted enol.

Under acid condition, Both intermediates are dehydrated, however, the branched-chain ketol is formed most rapidly, because of the preference for acid-catalyzed enolization to give the more substituted enol

majorforms rapidly

Base catalysis favors reaction at a methyl position over a methylene group,whereas acid catalysis gives the opposite preference.

2.1.3. Control of Regiochemistry and Stereochemistry of Mixed Aldol Reactions of Aliphatic Aldehyde and Ketones

2.1.3.1. Lithium Enolates Directed Aldol Reaction

Kinetic controlled conditions

Cyclic Transition State

E-enolate Anti-ketol

The enolate formed from 2,2-dimethyl-3-pentanone under kinetically controlledconditions is the Z-isomer. Reaction with benzaldehyde gives syn aldol.

When alkyl substituent of ketone is bulky, Z-enolate is formed. And syn-aldol product is formed. Order: t-butyl>i-propyl>ethyl

The enolate of cyclohexanone reacts with benzaldehyde are necessarilyE-isomers. Anti-isomer is major.

Because the aldol reaction is reversible, it is possible to adjust reaction conditions so that the two stereoisomeric aldol products equilibriate.

1) Z-enolate syn aldol; E-enolate anti aldol2) When the enolate has no bulky substituents, stereselectivity is low3) Z-enolates are more stereoselctive than E-enolates.Ref. Table 2.1

For synthetic efficiency, it is useful to add MgBr2.

The greater stability of the anti-isomer is attributed to the pseudoequitorial position of the methyl group in the chair-like chelate. With larger substituentgroups, the thermodynamic preference for the anti-isomer is still greater.

Ketones with one tertiary alkyl substituent give mainly the Z-enolate.However, less highly substituted ketones usually give mixtures of E- and Z-Enolates.

(1) Control of enolate stereochemistry(2) enhancement of the stereoselectivity in the addition step.

Control of stereochemistry of aldol reaction

For simple ester, the E-enolate is preferred under kinetic conditions using a strong base such as LDA in THF. But Inclusion of a strongcation sovating co-solvent, such as HMPA favors the Z-enolate.

With LDA/THF conditions, cyclic transition state, an open transition statein the presence of an aprotic dipolar solvent

Simple alkyl esters show rather low stereoselectivity.Highly hindered esters provide the anti-stereoisomers. See Table 2.2.

HMPA

Z-enolate Syn-major

If R= bulky, selectivity is increased

-alkoxy ester: higher stereoselectivity in some cases: it can be explained In terms of a chelated ester enolate. The aldehyde R group avoids being betweenthe -alkoxy and the methyl group in the ester enolate. When the ester alkyl groupR becomes very bulky, the stereoselectivity is reversed.

The allylic stabilization of the -deprotonation product can lead to kinetic selectivity in the deprotomation.

2.1.3.2. Boron Enolates

The stereoselctivity is higher than for lithium enolates, since the O-B bonddistances are shorter than the O-Li bond in the lithium enolates, and thisleads to a more compact transition state.

Trifluoromethanesulfonate = triflate

Z-isomer Syn-isomer

E-boron enolateAnti-isomer

Use of boron triflates with a more hindered amine favors the Z-enolate.The E-boron enolates of some ketone can be preferentially obtained with theuse of dialkylboron chlorides.

Z-enolate Cyclic mechanism for hydride transfer

E-boron enolateAnti-aldol product

Boron enolates parallel lithium enolates in their stereoselectivity but show enhanced stereoselectivity. (ref. table 2.3)

Cyclic transition state

N-acyloxazolidinone

2.1.3.3. Titanium, Tin, Zirconium Enolates: intermediate between Li+ and covalent boron enolate.

Z-enolateSyn-aldol

catalytic

Tin enolates

Syn-selectiveN-acylthiazolinethiones

E-enolates

(Cp)2ZrCl2 with lithium enolate

Addition of silyl enol ethers can be catalyzed by (Cp)2Zr2+ species.

The order of stereoselectivity is Bu2B>(Cp)2Zr>Li. These results are consistentWith reactions proceeding through a cyclic transition state.

2.1.3.4 The Mukaiyama Reaction: Lewis-acid-catalyzed aldol addition reactions of enol derivatives.

Not a strong enough nucleophile, but with Lewis acid the reaction proceeds through an acyclic transition state.

For -substituted aldehyde show a preference for a syn relationshipbetween the -substituent and hydroxy group. This is consistence witha Felkin-Ahn Transition state.

2.1.3.5. Control of Enantioselectivity

The combined interactions of chiral centers in both the aldehyde and theenolate determine the stereoselectivity. The result is called doublestereodifferentiation.

The oxazolinone substituents R’ direct the approach of the aldehyde.

2.1.4. Intramolecular Aldol Reaction and the Robinson Annulation

Robinson Annulation is a procedure which construct a new 6-memberedring from a ketone.

Originally thermodynamic controlled reaction is required.

The role of the trimethylsilyl group is to stabilize the enol formed in the conjugate addition. The silyl group is then removed during the dehydration step.It can be used under aprotic conditions.

The s-enantiomer of the product is obtained in high enantiomeric excess withL-proline,.

L-proline participates in the proton-transfer step.

2.2. Addition reactions of Imines and Iminium Ions.

The reactivity order is C=NR<C=O<[C=NR2]+<[C=OH]+.

2.2.1. the Mannich Reaction: the condensation of an enolizable carbonyl compound with an iminium ion.

The reaction is usually limited to secondary amines, because dialkylation canoccur with primary amines.

The dialkylation reaction can be used in ring closure.

Synthesis of Mannich base

Bis(methylamino)methane

N,N-Dimethylmethyleneammonium idode“Eschenmoser’s salt”

Thermal elimination of the amines or the derived quaternary salts provides-methylene carbonyl compounds.

Vernolepin having antileukemia activity

Tropinone, alkaloid tropine by Sir Rober Robinson in 1917

2.2.2. Amine-Catalyzed Condensation Reactions

Amine and acid are required: mixed aldol followed by dehydration:catalyzed by amine and buffer system: Knoevenagel condensation.

Malonic ester, cyanoacetic ester, cyanoamide are examples of compounds whichundergo condensation reactions under Knoevenagel conditions. Nitroalkanes arealso good nucleophilic reagent in which a hydrogens are deprotonated underweakly basic conditions.

Secondary amine is used as catalysts, iminium ion is involved in addition step.

Decarboxylative condensation is carried out in pyridine, which can notform an imine intermediate. concerted decarboxylation

2.3. Acylation of Carbanions

Ester self-condensation is Claisen Condensation.

Final step drives the reaction to completion.

Most acidic species

When -substituted ester are used, it do not condense under the normalreaction conditions. Very strong base converts the ester completely toits enolate.: sodium hydride

Intramolecular version of ester condensation is called the Dieckmanncondensation

Because ester condensation is reversible, product structure is governed bythermodynamic control: The product is derived from the most stable enolate.

Acylation of ester enolates can be carried out with more reactive acylating agentssuch as acid anhydrides and acyl chlorides: the reaction must be done in inertsolvents to avoid solvolysis of the acylating reagent.

N-methoxy-N-methylamides is also useful for acylation of ester enolates.

Sometimes O-alkylation is problem, magnesium enolates play an importantrole in C-acylation reaction.

Acyl imidazolides are more reactive than esters but not as reactive as acyl halides

2.4 The Wittig and Related Reactions

An ylide is a molecule that has a contributing Lewis structure with oppositecharges on adjacent atoms, each of which has an octet of electrons.

Phosporus ylides are stable, but usually quite reactive.

Organolithium compounds

Unstabilized ylides give predominantly the Z-alkene whearas stabilizedylides give mainly the E-alkene. Use of sodium amide or sodium hexa-methyldisilylamide as bases gives higher selectivity for Z-alkenes thanwith alkyllithium reagent as base.

The three phenyl substituents on phosphorus impose large steric demandswhich govern the formation of the diastereomeric adducts. Reactions of unstabilized phosphoranes are believed to proceed through an earlytransition state, and steric factors usually make such transition statesselective for the Z-alkene.

Schlosser modification of the Wittig reaction: the reaction of unstabilized ylidewith aldehyde can be induced to yield E-alkenes with high stereoselectivity.

Syn-elimination-oxido ylide

Phosphonoacetate esters are used to prepare -unsaturated esters: Wadsworth-Emmons reaction: usually lead to the E-isomer.

Three modified phosphonoacetate esters have been found to show selectivityfor the Z-enoate product. Trifluoroethyl, phenyl, 2,6-difluorophenyl estersgive good Z-stereoselectivity.

Carbanions derived form phosphine oxide add to carbonyl compounds. Theadducts are stable but undergo elimination to form alkenes on heating with abase such as sodium hydride.: Horner-Wittig reaction.

Usually anti-adduct is the major product, so it is the Z-alkene which is favored.The syn adduct is most easily obtained by reduction of -keto phosphine oxide.

2.5 Reactions of Carbonyl Compounds with a-trimethylsilylcarbanions

-Hydroxyalkyltrimethylsilanes are converted to alkenes in either acidic or basic solution. It begins with nucleophilic addition of an -trimethylsilyl-substituted carbanion to an aldehyde or ketone (Peterson reaction).

The separate elimination step is not necessary because fragmentation of theintermediate occurs spontaneously.

The elimination reactions are anti under acidic conditions and syn under basic conditions: the result of a cyclic elimination mechanism under basic conditions, whereas an acyclic -elimination under acidic conditions.

The anti-elimination can also be achieved by converting the -silyl alcoholto trifluoroacetate esters.

2.6 Sulfur Ylide and related Nucleophiles

Sulfur ylides are prepared by deprotonation of the corresponding sulfonium salts.

Phosphorus ylides + Ketone alkene Sulfonium or sulfoxonium ylides + ketone epoxide

Intramolecular displacement

Dimethylsulfonium metylide is less stable than dimethylsulfoxonium methylide, so it is generated and used at a low temperature.

2.7 Nucleophilic Addition-Cyclization

Darzens Reaction: The first step is addition of the enolate of the -halo ester to the carbonyl compound followed by intramolecular SN2 reaction.

Trimethylsilyl epoxide can be also preapred by an addition-cyclization process.