Alkylation of aldehydes and ketones

Halogenation Slows Down Enolization Because Protonation Is Disfavored 

Therefore, the singly halogenated product is not attacked by additional halogen until the starting aldehyde or ketone has been used up. 

Write the products of the acid- and base-catalyzed bromination of cyclohexanone. 

In Summary Halogenation of aldehydes and ketones in acid can proceed selectively to the monohalocarbonyl compounds. In base, all a-hydrogens are replaced before another molecule of starting material is attacked. 

We have seen that enolates may be generated from ketones and aldehydes by treatment with bases, such as LDA (Sections 7-8 and 18-1). The nucleophilic a-carbon of the enolate may participate in Sn2 alkylation reactions with suitable haloalkanes, forming a new carbon-carbon bond in the process. This section presents some features of enolate alkylation and compares it with a related process, alkylation of a species called an enamine. 

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OL Alkylation of aldehydes and ketones (Section 18.15) Alkylation of simple aldehydes and ketones via their enolates is difficult. p-Diketones can be converted quantitatively to their enolate anions, which react efficiently with primary alkyl halides. 

The reductive capability of CgK has been a subject of interest (LA). Uses for CgK include the reductive cleavage of carbon-sulfur bonds (S5), the reductive alkylation of nitriles and esters (S6), and the reductive alkylation of aldehydes and ketones (S7). The activity of CgK has... 

In summary, this organocatalytic alkylation of aldehydes and ketones is a promising route for preparation of optically active secondary and tertiary alcohols and is of general interest. Certainly, improvement of the asymmetric induction as well as applications of other nucleophiles will be the next major challenge in this field to make this synthetic concept competitive with alternative routes. 

Enamines like enolates are alkylated when treated with reactive alkylating agent, a-Substituted enamines can be converted into aldehydes and ketones by acid-catalyzed hydrolysis. Thus, in the three-step process, alkylation of aldehydes and ketones may be carried out via enamines (Stork enamine synthesis) (Scheme 3.19). 

The synthetic utility of the SAMP/RAMP hydrazone method is demonstrated in particular in the stereoselective alkylation of aldehyde and ketone SAMP/RAMP hydrazones. A great number of natural products have been synthesized using this method, like the principal alarm pheromone of the leaf cutting ant Atta texana (eq 1), the C(l)-C(15) segment of FK 506 (eq 2) the amino acid MeBMT (eq 3), and (-)-methyl kolavenate (eq 4). ... 

Scheme 3.21. Asymmetric alkylations of aldehydes and ketones with SAMP hydrazones.

Compared with other synthetic intermediates, enolates show a decreased reactivity. The differences in reactivity are most striking in reactions with alkylating agents [1] and epoxides [6]. The reactivities of the various types of enolates towards alkyl halides decrease in the order C=C(0 )NR2 (amide-enolate) C=C(0 )0R (ester enolate) C=CO (ketone-enolate). Metallated nitriles, imines, and S,S-acetals are, in general, much better nucleophiles than enolates in alkylations and ft-hydroxyalkylations [1], Furthermore, the alkylation of aldehyde and ketone enolates usually does not stop after the mono-functionalization [12]. The decreased reactivity of (especially) aldehyde and ketone enolates also appears in thiolations with disulfides [2]. A solution of lithiated cyclohexanone in THF does not react at 20°C with CH3SSCH3 [1,2]. 

A report has also appeared on the alkylation of aldehydes and ketones by polyfluoroalkoxyphosphoranes (62), which in the cases of paraformaldehyde, aromatic or unsaturated aldehydes, and hexafluoroacetone gives polyfluoro-alkyl-containing acetals [e.g., (63)]. 

Enamines and metalloenamines provide a valuable alternative to the use of eno-lates for the selective alkylation of aldehydes and ketones. Enamines are a,p-unsaturated amines and are obtained simply by reaction of an aldehyde or ketone with a secondary amine in the presence of a dehydrating agent, or by heating in benzene or toluene solution in the presence of toluene-/7-sulfonic acid (TsOH) as a catalyst, with azeotropic removal of water (1.31). Pyrrolidine and morpholine are common secondary amines useful for forming enamines. All of the steps of the reaction are reversible and enamines are readily hydrolysed by water to reform the carbonyl compound. All reactions of enamines must therefore be conducted under anhydrous conditions, but once the reaction has been effected, the modified carbonyl compound is liberated easily from the product by addition of dilute aqueous acid to the reaction mixture. 

Alkylation of lithiated hydrazones forms the basis of an efficient method for the asymmetric alkylation of aldehydes and ketones, using the optically active hydrazines (5)-l-amino-2-(methoxymethyl)pyrroUdine (SAMP) 59 and its enantiomer (RAMP) as chiral auxiliaries. Deprotonation of the optically active hydra-zones, alkylation and removal of the chiral auxiliary under mild conditions (ozonol-ysis or acid hydrolysis of the A-methyl salt) gives the alkylated aldehyde or ketone with, generally, greater than 95% optical purity. This procedure has been exploited in the asymmetric synthesis of several natural products. Thus, (S)-4-methyl-3-heptanone, the principal alarm pheromone of the leaf-cutting ant Am texana, was prepared from 3-pentanone in very high optical purity as shown in Scheme 1.74. 

Reductive alkylation of aldehydes and ketones essentially involves replacement of oxygen with two alkyl groups to furnish alkanes. The procedure can be employed advantageously for the conversion of ketones into em-dimethylated alkanes, a structural feature present in many natural products. Thus, several cyclic ketones have been transformed into m-dimethylated alkanes, employing mild conditions, with dimethyl-titanium dichloride (equation 68). m-Dimethylation of ketones has also been achieved by heating them with (CH3)3 A1 in the presence of AICI3 (equations 69 and 70). ... 

During the following several years, many examples of organocatalytic tandem reactions such as the intramolecular a-alkylation step were developed, but they are not subjected in this chapter [113]. Unlike any yet published example of intermolecular a-alkylation of aldehydes and ketones via an Sat2 mechanism, several works via the SAr2 -type addition-elimination pathway were disclosed to date. 

Asymmetric a-Alkylation of Aldehydes and Ketones via Organo-SOMO Catalysis... 

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

The stereoselective formation and reaction of hydrazone anions has been reported enantioselective alkylations of aldehydes and ketones (both cyclic and acyclic ) via their chiral hydrazones (97) are achieved in good yield and high optical purity (Scheme 71). 

The hydrazine SAMP, derived from (S)-proline, and its enantiomer RAMP were developed by EndersO ] for the asymmetric alkylation of aldehydes and ketones, and are commercially available, though expensive. The chiral auxiliary may be removed either by quatemisation with methyl iodide followed by hydrolysis, or by ozonolysis. 

In further studies on nucleophilic alkylation of aldehydes and ketones (to give secondary and tertiary alcohols, respectively) using alkyltitanium(iv) compounds, the e lier work on methyl tri-isopropoxytitanium (5,155) has been extended to other alkyl tri(alkoxy)titanium reagents. The observed chemoselec-tive addition to the aldehyde in benzaldehyde-acetophenone mixtures [equation (2)] illustrates that these systems are less reactive but more selective... 

In Chapter 1 we mentioned that efficient alkylation of aldehydes and ketones requires essentially quantitative formation of their enolates. When a low concentration of an enolate ion is generated, it may react more competitively with the parent aldehyde or ketone present in the reaction mixture than it does with an alkyl halide. The aldol condensation reaction is this acid- or base-catalyzed self-condensation of... 

Enamines afford an alternative route for the alkylation of aldehydes and ketones... 

Introduction The regiocontroUed a-alkylation of aldehydes and ketones focused tremendous attention between the 1950s and the 1970s [1], Fundamental solutions emerged... 

Conclusion The SAMP/RAMP hydrazone methodology developed by Enders almost 40 years ago dominated the field of diastereoselective a-alkylation of aldehydes and ketones. Due to its generality and robustness, this method cannot be circumvented. The recent development made by Coltart in 2008 is the first remarkable improvement since the initial discovery. 

Secondary and tertiary alcohols have been used for electrophilic a-alkylation of aldehydes and ketones. Highly stereoselective a-alkylations of R CHjCHO by R CHOHR have been achieved with 90-99% ee using a diarylprohnol silyl ether in combination... 

In contrast with carboxyl-derived enolates, few general, highly stereoselective methods for the asymmetric alkylation of aldehyde and ketone enolates are available [15, 20]. Some of the key problems associated with these are widely appreciated. The aldehyde and ketone counterparts are more weakly nucleophilic than carboxamide-derived enolates. In addition, the ease with which the products undergo epimerization under relatively mild acidic or alkaline conditions can provide a practical limit to the isolation of pure adducts. 

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