Lithium diisopropylamide preparation

Lithium acetyhde also can be prepared directly in hquid ammonia from lithium metal or lithium amide and acetylene (134). In this form, the compound has been used in the preparation of -carotene and vitamin A (135), ethchlorvynol (136), and (7j--3-hexen-l-ol (leaf alcohol) (137). More recent synthetic processes involve preparing the lithium acetyhde in situ. Thus lithium diisopropylamide, prepared from //-butyUithium and the amine in THF at 0°C, is added to an acetylene-saturated solution of a ketosteroid to directly produce an ethynylated steroid (138). 

To a solution of lithium diisopropylamide. prepared from 5.04 mL (35.6 mmol) of diisopropylamine, 22.3 mL (35.6 mmol) of a 1.6 M solution of butyllithium in hexane and 34 mL of THF at —78 C is added dropwise a solution of 5.44 g (32.4 mmol) of ( + )-l-[(R)-ethylsulfinyl]-4-methylbcnzene sulfoxide in 37 mL of THF. A suspension of lithium bromoacetate, prepared from 6.75 mL (48.6 mmol) of bromoacetic acid and 5.15 g (64.84 mmol) of lithium hydride in 50 mL of THF, is added at the same temperature to the yellow solution of the sulfinyl anion. The mixture is stirred for 5 min at — 78 °C, sat. aq NH4C1 is added, and then 10 M hydrochloric acid is added dropwise until the solution reaches pH 2. The mixture is extracted with ethyl acetate, the extracts are concentrated, chromatography of the residue gives the product yield 4.24 g (58%) mp 53-55rC (hexane/diethyl ether). 

A solution of ethyl 2-ethylbutyrate (150 mmol) dissolved in 25 ml THF was added dropwise to a solution of lithium diisopropylamide (prepared by treating diisopropylamine (165 mmol) dissolved in 150 ml THF with butyllithium in hexanes (165 mmol) at —78°C 1 hour) in a nitrogen atmosphere and stirred 1 hour. Thereafter, bromoacetonitrile (180 mmol) dissolved in 50 ml THF was added over 30 minutes and the mixture stirred overnight at —78°C. The reaction was quenched with 250 ml IM HCl, the layers separated, and the aqueous phase extracted 3 times with 100 ml diethyl ether. The extracts... 

Metalation of 3-methylquinoxalin-2(l//)-one with lithium diisopropylamide prepared in situ affords the dianion in good yield. 

Under stirring, a precooled solution of 2-bromo-3,3,3-trifluoropropene (3.5 g, 20 mmol) in tetrahydrofuran is added dropwise to a solution of lithium diisopropylamide (prepared from disopropylamine and -butyllithium, 20 mmol each) in tetrahydrofuran (40 mL) and hexanes (25 mL) kept in a dry ice/methanol bath. After another 5 min at -75 °C, 3-benzyloxypropanal (3.3 g, 20 mmol) is added. The mixture is allowed to reach ambient temperature before being treated with 1.0 M hydrochloric acid (25 mL), extracted with ethyl acetate (3 x 15 mL), and concentrated. The combined organic layers are evaporated and the residue left behind is purified by column chromatography on silica gel 4.76 g (92%). ... 

A solution of 2-methylcycloheanone (11.2 g, 100 mmol) in THF (10 mL) is added to a stirred solution of lithium diisopropylamide [prepared in situ by addition of a 1.6-M solution of -butyllithium (66 mL, 106 mmol) in hexane to diisopropylamine (16.8 mL, 120 mmol) in dry THF (240 mL) at -78 C] under a nitrogen atmosphere at -78 °C over 10 min. The solution is stirred for a further 1 h, then chlorotrimethylsilane (22 mL, 170 mmol) is added over 5 min. The solution is allowed to warm to rt and, after being stirred for 1 h, the solvent is evaporated in vacuo. Dry pentane (100 mL) is added and LiCl thus precipitated is removed by filtration. The filtrate is concentrated in vacuo, refiltered (if necessary), and distilled (bp 59-61 °C at 7 mmHg) to give the title compound in 97% yield. ... 

Lithium diisopropylamide is commercially available Alternatively it may be prepared by the reaction of butyllithium with [(CH3)2CH]2NH (see Problem 14 4a for a related reaction)... 

Many organic syntheses requHe the use of stericaHy hindered and less nucleophilic bases than //-butyUithium. Lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LHS) are often used (140—142). Both compounds are soluble in a wide variety of aprotic solvents. Presence of a Lewis base, most commonly tetrahydrofuran, is requHed for LDA solubdity in hydrocarbons. A 30% solution of LHS can be prepared in hexane. Although these compounds may be prepared by reaction of the amine with //-butyUithium in the approprite medium just prior to use, they are also available commercially in hydrocarbon or mixed hydrocarbon—THF solvents as 1.0—2.0 M solutions. 

Although less researched than the 2-position, modifications at the 6-position of intact penems have been reported. Generation of the dianion of the penem (52, R = CH ) using a strong base such as / -butyUithium or lithium diisopropylamide, followed by reaction with electrophiles yields 6-substituted 2-methylpenems in moderate yield (128). The enhanced acidity of the 6-proton in the bromopenem (88) [114409-16-4] h.a.s been exploited to prepare the... 

Side-chain lithiation with lithium diisopropylamide and subsequent alkylation or acylation is a practical method for the preparation of various alkyl-, alkenyl- and acyl-methyl-pyridazines 78CPB2428, 78CPB3633, 79CPB916) (Scheme 47). 

N-Alkylations, especially of oxo-di- and tetra-hydro derivatives, e.g. (28)->(29), have been carried out readily using a variety of reagents such as (usual) alkyl halide/alkali, alkyl sulfate/alkali, alkyl halide, tosylate or sulfate/NaH, trialkyloxonium fluoroborate and other Meerwein-type reagents, alcohols/DCCI, diazoalkanes, alkyl carbonates, oxalates or malon-ates, oxosulfonium ylides, DMF dimethyl acetal, and triethyl orthoformate/AcjO. Also used have been alkyl halide/lithium diisopropylamide and in one case benzyl chloride on the thallium derivative. In neutral conditions 8-alkylation is observed and preparation of some 8-nucleosides has also been reported (78JOC828, 77JOC997, 72JOC3975, 72JOC3980). 

Most applications of this derivative have been for the preparation and modification of amino acids, although some applications in the area of carbohydrates have been reported. The derivative is stable to n-butyllithium and lithium diisopropylamide. 

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. 

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... 

Having retraced the remarkably efficient sequences of reactions which led to syntheses of key intermediates 14 and 15, we are now in a position to address their union and the completion of the synthesis of the spiroketal subunit (Scheme 6b). Regiocontrolled deprotonation of hydrazone 14 with lithium diisopropylamide (LDA), prepared from diisopropylamine and halide-free methyl-lithium in ether, furnishes a metalloenamine which undergoes smooth acylation when treated with A-methoxy-A-methylcarboxa-mide 15 to give the desired vinylogous amide 13 in 90% yield. It is instructive to take note of the spatial relationship between the... 

Several reviews cover hetero-substituted allyllic anion reagents48-56. For the preparation of allylic anions, stabilized by M-substituents, potassium tm-butoxide57 in THF is recommended, since the liberated alcohol does not interfere with many metal exchange reagents. For the preparation of allylic anions from functionalized olefins of medium acidity (pKa 20-35) lithium diisopropylamide, dicyclohexylamide or bis(trimethylsilyl)amide applied in THF or diethyl ether are the standard bases with which to begin. Butyllithium may be applied advantageously after addition of one mole equivalent of TMEDA or 1,2-dimethoxyethane for activation when the functional groups permit it, and when the presence of secondary amines should be avoided. 

However, deprotonation of rc-rf-butyldimethylsilyl-protected products 2 (prepared according to the classical Henry conditions )22, and consecutive reprotonation, provides the silylated nitroaldols 2 with high (R, R ) selectivity. Deprotonation of 2 by treatment with lithium diisopropylamide in tetrahydrofuran at — 78 C furnishes nitronates which are stable against / -elimination at that temperature. Protonation of these intermediates is achieved with an acetic acid/tetrahydrofuran (1 1) solution at —100 C. To achieve maximum yields, the mixture should be warmed up slowly before aqueous workup. 

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. 

The starting materials for annulative cyclization are cycloalkenones that contain the allylsilane side chain in the 4-position. Such starting materials can easily be prepared from vinylogous esters40. Furthermore, reactions of 3-alkoxy-2-cyclohexenones with functionalized iodides in the presence of lithium diisopropylamide provides an excellent route to such precursors41 34 35. 

When 2,2-dimethylpropanal is used to prepare the azomethine moiety, the corresponding azaallyl anion may be obtained when l,8-diazabicyclo[5.4.0]undec-7-ene/lithium bromide is used as base. The subsequent addition to various enones or methyl ( )-2-butenoate proceeds with anti selectivity, presumably via a chelated enolate. However, no reaction occurs when triethylamine is used as the base, whereas lithium diisopropylamide as the base leads to the formation of a cycloadduct, e.g., dimethyl 5-isopropyl-3-methyl-2,4-pyrrolidinedicarboxylate using methyl ( )-2-butenoate as the enone84 89,384. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

As first described by Krizan and Martin,6 the in situ trapping protocol, i.e., having the base and electrophile present in solution simultaneously, makes it possible to lithiate substrates that are not applicable in classical ortho-lithiation reactions.7 Later, Caron and Hawkins utilized the compatibility of lithium diisopropylamide and triisopropyl borate to synthesize arylboronic acid derivatives of bulky, electron deficient neopentyl benzoic acid esters.8 As this preparation illustrates, the use of lithium tetramethylpiperidide instead of lithium diisopropylamide broadens the scope of the reaction, and makes it possible to functionalize a simple alkyl benzoate.2... 

The enol acetates, in turn, can be prepared by treatment of the parent ketone with an appropriate reagent. Such treatment generally gives a mixture of the two enol acetates in which one or the other predominates, depending on the reagent. The mixtures are easily separable. An alternate procedure involves conversion of a silyl enol ether (see 12-22) or a dialkylboron enol ether (an enol borinate, see p. 560) to the corresponding enolate ion. If the less hindered enolate ion is desired (e.g., 126), it can be prepared directly from the ketone by treatment with lithium diisopropylamide in THE or 1,2-dimethoxyethane at —78°C. ... 

Method C High awft -selectivity is also observed in the fluoride-catalyzed reaction of silyl nitronates with aldehydes. Trialkyl silyl nitronates are prepared in good yield from primary nitroalkanes by consecutive treatment with lithium diisopropylamide and trialkylsilyl chloride at -78 °C in THF. 

A route for the asymmetric synthesis of benzo[3]quinolizidine derivative 273 was planned, having as the key step a Dieckman cyclization of a tetrahydroisoquinoline bis-methyl ester derivative 272, prepared from (.S )-phcnylalaninc in a multistep sequence. This cyclization was achieved by treatment of 272 with lithium diisopropylamide (LDA) as a base, and was followed by hydrolysis and decarboxylation to 273 (Scheme 58). Racemization could not be completely suppressed, even though many different reaction conditions were explored <1999JPI3623>. 

Bu3SnCHBr2 was prepared from CH2Br2, BusSnCl and lithium diisopropylamide, LDA. 

Deprotonation readily occurs at C-7, and the resulting anion can further react with various electrophiles. Thus, treatment with BuLi at — 78 °C followed by reaction with diiodoethane was used to prepare the 7-iodo derivatives depicted in Table 2, while the 7-chloro derivatives were prepared by lithiation with lithium diisopropylamide (LDA), followed by reaction with CCI4. The 7-formyl derivative of the parent pyrazolo[l,5- ]pyridine has been prepared in 82% yield by reaction of the BuLi-generated anion with ethyl formate <2001JME2691>. 

Generation in situ. Butyllithium (primary, secondary, or tertiary) can be generated by sonication of a mixture of lithium wire and a butyl chloride at 15° in dry THF. The corresponding butane is evolved under these conditions and LiCl precipitates the reaction is generally complete within 15 min. The highly useful lithium diisopropylamide can be prepared by sonication of a mixture of diisopropylamine, lithium, and butyl chloride in dry THF or ether. The yield is 91% and the solution can be used directly for deprotonation. Other lithium amides, even LiTMP, can be prepared in the same way. 

Further variations of the Claisen rearrangement protocol were also utilized for the synthesis of allenic amino acid derivatives. Whereas the Ireland-Claisen rearrangement led to unsatisfactory results [133b], a number of variously substituted a-allenic a-amino acids were prepared by Kazmaier [135] by chelate-controlled Claisen rearrangement of ester enolates (Scheme 18.47). For example, deprotonation of the propargylic ester 147 with 2 equiv. of lithium diisopropylamide and transmetallation with zinc chloride furnished the chelate complex 148, which underwent a highly syn-stereoselective rearrangement to the amino acid derivative 149. 

A reported procedure based on lithium diisopropylamide induced double elimination of ethanol from bromoacetaldehyde diethyl acetal also was not very effective for the large scale preparation of phenylthioacetylene.8 Another more recent synthesis of the title compound relies on the reaction of dimethyl(chloroethynyl)carbinol with an alkali metal phenylthiolate, followed by... 

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). 

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