Carbonyl compounds lithium diisopropylamide

Common reagents such as lithium diisopropylamide (LDA see Chapter 11, Problem 5) react with carbonyl compounds to yield lithium enolate salts and diisopropylamine, e.g., for reaction with cyclohexanone. 

Because carbonyl compounds are only weakly acidic, a strong base is needed for enolate ion formation. If an alkoxide such as sodium ethoxide is used as base, deprotonation takes place only to the extent of about 0. l% because acetone is a weaker acid than ethanol (pKa - 16). If, however, a more powerful base such as sodium hydride (NaH) or lithium diisopropylamide ILiNO -CjHy ] is used, a carbonyl compound can be completely converted into its enolate ion. Lithium diisopropylamide (LDA), which is easily prepared by reaction of the strong base butyllithium with diisopropylamine, is widely used in the laboratory as a base for preparing enolate ions from carbonyl compounds. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

There is no simple answer to this question, but the exact experimental conditions usually have much to do with the result. Alpha-substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature. An electrophile is then added rapidly to ensure that the reactive enolate ion is quenched quickly. In a ketone alkylation reaction, for instance, we might use 1 equivalent of lithium diisopropylamide (LDA) in lelrahydrofuran solution at -78 °C. Rapid and complete generation of the ketone enolate ion would occur, and no unreacled ketone would be left so that no condensation reaction could take place. We would then immediately add an alkyl halide to complete the alkylation reaction. 

Treatment of a-dichloromethyl phenyl sulfoxide with lithium diisopropylamide in THF gave monolithiated derivative 122, which upon further treatment with aldehyde afforded the )S-hydroxy-a-dichlorosulfoxide 123. Thermolysis of 123 gave dichloroketone 124, by extruding benzenesulfenic acid as shown below . Similarly, in the reaction of lithio-a-fluoromethyl phenyl sulfoxide and aldehyde, fluoromethyl ketone 126 was obtained, after thermolysis of the hydroxy intermediate 125. Diethylphosphorylmethyl methyl sulfoxide was shown by Miko/ajczyk and coworkers to be lithiated with n-BuLi to intermediate 127, which upon treatment with carbonyl compounds afforded the corresponding a, -unsaturated sulfoxides 128 in good yields. 

Another type of sp -hybridized S-oxido functionahzed organolithium compounds has been easily prepared from chloroacetic acid (149). After a double deprotonation with lithium diisopropylamide in THF at —78°C, a DTBB catalyzed (5%) hthiation in the presence of different carbonyl compounds as electrophiles at the same temperature followed by final hydrolysis afforded the expected S-hydroxy acids 151. The corresponding intermediate 150 was probably involved in the process (Scheme 54)" . 

Reaction of 3-trifluoromethyl-substituted 1,2-oxazine 5 with lithium diisopropylamide (LDA) resulted in smooth deprotonation at C-4 and allowed subsequent alkylation with various electrophiles. Reaction of 5 with Mel furnished the 4-methyl-l,2-oxazine 54 in good yield and with excellent r-diastereoselectivity, whereas carbonyl compounds could not be employed successfully as electrophiles <1996JFC( 80)21 1 reatment of 3,4,6-trisubstituted l,2"Oxazine... 

The key reagents for the deprotonation of esters, acids and carbonyl compounds in general are the hindered metal amides, such as lithium diisopropylamide (1), lithium cyclohexyliso-propylamide (2) and lithium, sodium and potassium hexamethyldisilazanides (3). 

Lithium diisopropylamide, 163 Phenyl azide-Aluminum chloride, 240 Halo carbonyl compounds (see also Unsaturated carbonyl compounds) a-Chloro acids Sodium nitrite, 282 a-Halo aldehydes and ketones... 

A new method of kinetically controlled generation of the more substituted enolate from an unsymmetrical ketone involves precomplexation of the ketone with aluminium tris(2,6-diphenylphenoxide) (ATPH) at —78°C in toluene, followed by deprotonation with diisopropylamide (LDA) highly regioselective alkylations can then be performed.22 ATPH has also been used, through complexation, as a carbonyl protector of y./)-unsaturated carbonyl substrates during regioselective Michael addition of lithium enolates (including dianions of /i-di carbonyl compounds).23... 

The methylene group adjacent to the carbonyl group in a /3-lactam is weakly acidic and compound 164 was alkylated to give 165 by the action of lithium diisopropylamide (LDA) and acetyl trimethylsilane (Equation 18) <1996TL2467>. 

E -Enolates often react with lower stereoselectivity than those of the corresponding Z-enolates. A classic example to illustrate this point is a study carried out by Heathcock et al.6 (Scheme 2.IV). When the carbonyl compounds 1 were deprotonated with lithium diisopropylamide (LDA) and the resulting enolates were subsequently treated with benzaldehyde at -72° C, the aldol products desired (2) were obtained in 83 to 99% yield. The Z-enolates derived from t -butyl and 1-adamantyl ethyl ketones afforded syn -products in excellent levels of diastereoselectivity. The fact that the syn/anti ratios directly reflect the isomeric purity of the reacting enolates hints that the Z-enolates in these cases undergo aldol reaction through a chairlike six-membered transition state (Scheme 2.III,... 

Sometimes this equilibrium mixture of enolate and base won t work, usually because the base (hydroxide or alkoxide) reacts with the electrophile faster than the enolate does. In these cases, we need a base that reacts completely to convert the carbonyl compound to its enolate before adding the electrophile. Although sodium hydroxide and alkoxides are not sufficiently basic, powerful bases are available to convert a carbonyl compound completely to its enolate. The most effective and useful base for this purpose is lithium diisopropylamide (LDA), the lithium salt of diisopropylamine. LDA is made by using an alkyllithium reagent to deprotonate diisopropylamine. 

Lithium diisopropylamide (LDA), LiN(i-Pr)2 Reacts with carbonyl compounds (aldehydes, ketones, esters) to yield enolate ions (Sections 22.5 and 22.7). 

Modified Peterson reaction. This reagent was used in an unusual application of the Peterson reaction. The a-trirtiethylsilyloxy aldehyde (1) was converted in 80% yield to the Ws-trimethylsilyl compound (2) by treatment at - 35" with 0.95 equiv. of trimethylsilyllithium in HMPT. Nucleophilic attack at the carbonyl carbon was followed by silicon migration to the secondary alkoxide. The reaction of 2 with 3 equiv. of lithium diisopropylamide in THE containing 5% HMPT at 23" gave the saturated aldehyde 3 in 80% yield. The reaction was used to convert a hindered >C=0 into >CHCH20H. 

Amide Enolates. The lithium (Z)-enolate can be generated from (5)-4-benzyl-3-propanoyl-2,2,5,5-tetra-methyloxazolidine and Lithium Diisopropylamide in THF at —78 °C. Its alkylations take place smoothly in the presence of Hexamethylphosphoric Triamide with high diastereoselec-tivity (eq 3), and its Michael additions to a,(3-unsaturated carbonyl compounds are also exclusively diastereoselective (eq 4). Synthetic applications have been made in the aldol reactions of the titanium (Z)-enolates of a-(alkylideneamino) esters. ... 

Aldol-iype Condensation. Dimetalation of (R)-(+)-3-(p-tolylsulfinyl)propionic acid with Lithium Diisopropylamide produces a chiral homoenolate dianion equivalent which reacts with carbonyl compounds to afford p-sulfinyl-y-hydroxy acids these spontaneously cyclize to give the corresponding p-sulfinyl 7-lactones (eq 2) ... 

The ylid 371 prepared by treating cyclopropyltriphenylphosphonium bromide (with lithium diisopropylamide (LDA) produces a useful synthon on reaction with ethyl chloroformate . The fluoroborate salt (372) was shown to be an excellent reagent for cycloalkenylation of carbonyl compounds. The ylid was used successfully in the total synthesis of Spirovetivanes. ... 

Lithium diisopropylamide (LDA) is easily prepared by reaction betweea butyliithium (BuLi) and diisopropyiamine and is widely used as a base fin preparing enolate ions from carbonyl compounds. LDA has nearly ideal properties ... 

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