Diisopropylamide, reactions

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... 

There are some recent examples of this type of synthesis of pyridazines, but this approach is more valuable for cinnolines. Alkyl and aryl ketazines can be transformed with lithium diisopropylamide into their dianions, which rearrange to tetrahydropyridazines, pyrroles or pyrazoles, depending on the nature of the ketazlne. It is postulated that the reaction course is mainly dependent on the electron density on the carbon termini bearing anionic charges (Scheme 65) (78JOC3370). 

The reaction of 3,5-diphenyl-2-isoxazoline with lithium diisopropylamide produced with 2 equivalents of base a chalcone oxime, while in the presence of 1 equivalent and an alkyl iodide, ring alkylation occurred at the 4-position of the nucleus (Scheme 48) (80LA80, 78TL3129). 

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. 

In general the reaction of an aldehyde with a ketone is synthetically useful. Even if both reactants can form an enol, the a-carbon of the ketone usually adds to the carbonyl group of the aldehyde. The opposite case—the addition of the a-carbon of an aldehyde to the carbonyl group of a ketone—can be achieved by the directed aldol reaction The general procedure is to convert one reactant into a preformed enol derivative or a related species, prior to the intended aldol reaction. For instance, an aldehyde may be converted into an aldimine 7, which can be deprotonated by lithium diisopropylamide (EDA) and then add to the carbonyl group of a ketone ... 

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. 

Still s synthesis of monensin (1) is based on the assembly and union of three advanced, optically active intermediates 2, 7, and 8. It was anticipated that substrate-stereocontrolled processes could secure vicinal stereochemical relationships and that the coupling of the above intermediates would establish remote stereorelationships. Scheme 3 describes Still s synthesis of the left wing of monensin, intermediate 2. This construction commences with an aldol reaction between the (Z) magnesium bromide enolate derived from 2-methyl-2-trimethylsilyloxy-3-pentanone (21) and benzyloxymethyl-protected (/ )-/ -hydroxyisobutyraldehyde (10).2° The use of intermediate 21 in aldol reactions was first reported by Heathcock21 and, in this particular application, a 5 1 mixture of syn aldol diastereoisomers is formed in favor of the desired aldol adduct 22 (85% yield). The action of lithium diisopropylamide (LDA) and magnesium(n) bromide on 21 affords a (Z) magnesium enolate that... 

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... 

Eq. (3), with lithium diisopropylamide (LDA) to a lithiospecies and in its subsequent reaction with C02 affording via the corresponding 4-carboxylic acid its ethyl ester 59. In the alternative version perchlorate 48e is electro-chemically reduced in acetonitrile to an anionic species that was converted either to a 3 1 mixture of isomers 56 (R = f-Bu) and 60 or to 4//-thiopyran 56 (R = PhCH2) with f-BuI or PhCH2Br, respectively (90ACS524). The kinetics of the benzylation procedure was followed by cyclic voltammetry [88ACS(B)269]. 

Very high levels of induced diastereoselectivity are also achieved in the reaction of aldehydes with the titanium enolate of (5)-l-rerr-butyldimethylsiloxy-1-cyclohexyl-2-butanone47. This chiral ketone reagent is deprotonated with lithium diisopropylamide, transmetalated by the addition of triisopropyloxytitunium chloride, and finally added to an aldehyde. High diastereoselectivities are obtained when excess of the titanium reagent (> 2 mol equiv) is used which prevents interference by the lithium salt formed in the transmetalation procedure. Under carefully optimized conditions, diastereomeric ratios of the adducts range from 70 1 to >100 1. 

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. 

Metalation ofa-sulfinyl dimethylhydrazones with terf-butylmagnesium bromide, butyllithium or lithium diisopropylamide, and reaction of the generated azaenolates with aldehydes, provides aldol adducts (e.g., 6) as mixtures of diastereomers. Reductive desulfurization leads to fi-hydroxy dimethylhydrazones (e.g., 7) which are cleaved to the desired /(-hydroxy ketones in 25% overall yield10 u. The enantiomeric excesses are about 50%, except for (- )-3-hydroxy-4-methyl-1-phenyl-1-pentanone (8) which was obtained in 88% ee. 

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 metallation of 1,3-diselenanes is complex. When potassium diisopropylamide is used as base, deprotonation and alkylation affords the 2-equatorially substituted derivative <96TL2667>. However, with rertbutyllithium, Se-Li exchange is observed in preference to H-Li exchange in the reaction with 2-ox-methylseleno derivatives <96TL8015>. The reaction with nBuLi either forms the anion or cleaves a C-Se bond depending on the substituents present at the 2-, 4- and 6- positions <96TL8011>. 

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. 

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