Condensation lithium diisopropylamide

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. 

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

Chiral oxazolidines 6, or mixtures with their corresponding imines 7, are obtained in quantitative yield from acid-catalyzed condensation of methyl ketones and ( + )- or ( )-2-amino-l-phcnylpropanol (norephedrine, 5) with azeotropic removal of water. Metalation of these chiral oxazolidines (or their imine mixtures) using lithium diisopropylamide generates lithioazaeno-lates which, upon treatment with tin(II) chloride, are converted to cyclic tin(II) azaenolates. After enantioselective reaction with a variety of aldehydes at 0°C and hydrolysis, ft-hydroxy ketones 8 are obtained in 58-86% op4. 

Table 10 shows examples of. vvn-sclcctive enolate condensations with imines using different types of enolates. All enolates used in these experiments were prepared based on the corresponding lithium enolate by treatment with different Lewis acids, where the lithium enolates themselves were generated with lithium diisopropylamide (LDA) at — 78 °C. 

Ethyl 3-oxoalkanoates when not commercially available can be prepared by the acylation of tert-butyl ethyl malonate with an appropriate acid chloride by way of the magnesium enolate derivative. Hydrolysis and decarboxylation in acid solution yields the desired 3-oxo esters [59]. 3-Keto esters can also be prepared in excellent yields either from 2-alkanone by condensation with ethyl chloroformate by means of lithium diisopropylamide (LDA) [60] or from ethyl hydrogen malonate and alkanoyl chloride usingbutyllithium [61]. Alternatively P-keto esters have also been prepared by the alcoholysis of 5-acylated Mel-drum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione). The latter are prepared in almost quantitative yield by the condensation of Meldrum s acid either with an appropriate fatty acid in the presence of DCCI and DMAP [62] or with an acid chloride in the presence of pyridine [62] (Scheme 7). 

The kinetic enolization of esters with amide bases such as lithium diisopropylamide (LDA) and the resultant aldol condensations with representative aldehydes have been investigated by several groups (2,32,33). The enolate stereochemical assignments were determined by silylation in direct analogy to studies reported by Ireland (34). The preponderance of (E )-enolate observed with LDA (THF) in these... 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

The constrained bis(oxazolines) 9a and 9b can be constructed beginning with malononitrile 32 as shown by Ghosh and co-workers. Thus, treatment of 32 with anhydrous hydrochloric acid in dioxane, as shown by Lehn and co-workers, yielded imidate salt 33 (Fig. 9.9). Condensation of the imidate salt with commercially available (15,2/ )-l-aminoindan-2-ol afforded the conformationally constrained bis(oxazoline) inda-box 9a. Alkylation at the bridging methylene of 9a was carried out by Davies and co-workers.Treatment of 9a with lithium diisopropylamide followed by alkylation with methyl iodide afforded 9b. Alternatively, alkylation with diiodoalkanes incorporated ring systems at the bridging position (structures 34a-d). 

Lithium diisopropylamide complexed with HMPA will give the lithium derivative of 3-picoline and of 3-methylquinoline, and the products have been condensed with a variety of electrophiles (e.g. Scheme 58) (76JOC716, 75S705). 

An oven-dried. 50-mL, 3-necked flask equipped wilh a pressure-equalizing dropping funnel, reflux condenser, nitrogen inlet, magnetic stirrer, and vacuum takeoff adapter is evacuated (vacuum pump) and refilled three times with nitrogen. 10 mL of THF and 0.735 mL (5.25 mmol) of diisopropylamine are then added via a double-ended needle. The solution is cooled to 0"C and 2.2 mL of a 2.4 M solution of butyllithium (5.25 mmol) in hexane are added. The lithium diisopropylamide is allowed to form at 0 °C for 15 min and is then cooled to — 20 C. 5 mmol of the chiral acyclic ketone iminc in 5 mL of THF are added (5 min) and anion formation allowed to continue for 1 h at 20 C. The anion solution is then heated to reflux for 2 h and cooled to —78 C. A solution of 5.25 mmol of the iodoalkane in 5 mL of THF is then added, and alkylation is allowed to proceed at — 78 °C for 1 h. Workup and hydrolysis, as described for the cyclic ketones (see Section 1.1.1.4.1.2.L), yields the a-alkylatcd acyclic ketones (see Table 4). 

In 2001, Sierra and coworkers have reported that ethyl 3-ferrocenylpropanoate reacting with an excess of lithium diisopropylamide (LDA) afforded an enolate that condensed with imine the resulting reaction mixture contained the expected 2-azetidinone as a cisltrans mixture (3 1), and the unexpected 3-hydroxy p-lactam [136]. The ferrocene moiety was linked to the p-lactam ring at the C-3 position, (Scheme 51). 

Esters of 2-(2-methylphenyl)hydrazinecarboxylic acids can be metallated with lithium diisopropylamide (LDA) and the resulting polyanions condensed with aromatic esters and lead to acid-catalysed cyclization to 1-isoquinolones... 

Recool the resultant lithium diisopropylamide (LDA) solution to -78°C with the liquid N2/petroleum ether bath. Condense the 2-hydropentafluoro-propene into the stirred LDA solution slowly, so as to maintain a temperature of -78°C to -80°C. After addition is complete, continue stirring the orange coloured solution of CF3(Li)C=CF2 for 30 min at -78°C. 

The monoadduct (I) contains a terminal vinyl group and a secondary amine function. Thus, self-condensation appears to be possible. Lithium diisopropylamide was used to create the amide function, instead of butyllithium which could possibly attack the double bond. Thus, the metalation of the secondary amine function is straightforward, and the occurring self-condensation can be monitored by 13C-NMR and by GPC. No side reaction has been detected. This process can be illustrated by the following scheme ... 

Synthesis routes used in the work involved condensation of l-benzyl-4-piperidone with an appropriately substituted propionamide promoted by a strong base (lithium diisopropylamide, LDI), with subsequent alkylation of anilino nitrogen (if necessary) and replacement of N-benzyl by the 2-arylethyl substituent. Direct use of the N-arylethyl-4-piperidone was also made. 

ALDOL CONDENSATION (+)-(R)-l-Amino-2- methoxymethyl)pyrrolidine. Boron trichloride. Dialkylboron tri-fluoromethanesulfonates. Dibenzyl-ammonium trifluoroacetate. Di- -butylboryl trifluoromethanesulfonate. Dichlorodiethylaminoborane. Diiso-propylaluminum phenoxide. Diisopropyl-aminomagnesium bromide. Lithium diisopropylamide. Morpholine-Camphoric acid. Proline. 

In an asymmetric approach to the bicyclo[2.2.2]octane ring system, a double Michael addition has been employed using phenylmenthyl acrylate as the initial Michael acceptor. The condensation of the dienolate, generated with Lithium Diisopropylamide, reacts with the acrylate to afford the bicyclo[2.2.2]octane derivative (eq 6). The de for the reaction is only 50% however, it is highly endo selective (>95%). ... 

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) ... 

To a solution of lithium diisopropylamide (4.4 mmol) in dimethoxyethane (DME) (12 mL), in a flask equipped with a reflux condenser and a septum inlet was added a solution of 2-allyl-2-carbomethoxycycloheptanone (4 mmol) in DME (8 mL) at — 78 °C. Then, a solution of PhN(Tf)2 (4.28 mmol) in DME (8 mL) was added. After 30 min, at — 78 °C, the reaction mixture was allowed to stand at 0°C overnight. The solution was diluted with benzene, washed with aqueous 10% NaHCOj and brine, and finally dried over MgS04. Chromatography over silica gel with hexane/ether (30 1) gave the enol triflate (0.854 g, 60% yield). 

Acylation of 3,4,7,8-tetramethylglycoluril by the method of Sun and Harrison [34] leads to the monoacyl derivatives, which can be further selectively acylated with lithium diisopropylamide (LDA) and acyl chlorides. The resulting symmetrical or asymmetrical diacyl compounds undergo a base-catalyzed acyl transfer reaction. Consequently, the glycoluril acts as a temporary template that facilitates a condensation between acyl units. The absence of O-acylation products is explained by chelation of the lithium by the intermediate enolate. 

---