Deprotonation lithium diisopropylamide

Although the regioselectivity of the alkylation reaction is independent of the nature and the steric bulk of the electrophile, it is dependent on the steric bulk of the base used for deprotonation. Lithium diisopropylamide (LDA) is superior for endo deprotonation, whereas exo dcprotonation is best achieved with the sterically hindered lithium 2,2,6,6-tetramethylpiperidide (LTMP)11,16. 

Cu(I)-complexed [2]-rotaxane 96 was synthesized as follows (Figure 2.32)16f 67 2-rnethy l-9-(p-anisy I)-1, 10-phenanthroline 91 was deprotonated (lithium diisopropylamide) and the resulting anion was alkylated with the... 

Section 21 10 It is possible to generate ester enolates by deprotonation provided that the base used is very strong Lithium diisopropylamide (LDA) is often used for this purpose It also converts ketones quantitatively to their enolates... 

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 ... 

Good yields are usually obtained with aromatic aldehydes or ketones. Aliphatic aldehydes are poor substrates for the ordinary procedure, but react much better if the halo ester is first deprotonated with lithium diisopropylamide (LDA) in tetrahydrofuran at -78 °C, prior to addition of the aldehyde. 

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... 

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. 

The induced stereoselectivity in these aldol additions with (///S)-2Tiydroxy-l,2,2-triphenylethyl acetate is improved by the use of an excess of base (e.g.. 3 equiv of lithium diisopropylamide or lithium hexamethyldisilazane) in the deprotonation step89. 

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. 

Ethyl (bornylideneamino)acetate (2) and the imines of (-)-(lf ,2, 5 )-2-hydroxy-3-pinanone and glycine, alanine and norvaline methyl esters were particularly successful as Michael donors. The chiral azaallyl anions, derived from these imines by deprotonation with lithium diisopropylamide in THF at — 80 C, add to various a,/i-unsaturated esters with modest to high diastereoselectivity (see Section 1.5.2.4.2.2.5.). Thus, starting with the imine 2, (R1 = CH,) and ethyl ( )-2-butcnoate, the a,/i-dialkylated glutamate derivative 3 is obtained as a single diastercomer in 90% yield91-92. 

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. 

Oxo esters are accessible via the diastereoselective 1,4-addition of chiral lithium enamine 11 as Michael donor. The terr-butyl ester of L-valine reacts with a / -oxo ester to form a chiral enamine which on deprotonation with lithium diisopropylamide results in the highly chelated enolate 11. Subsequent 1,4-addition to 2-(arylmethylene) or 2-alkylidene-l,3-propanedioates at — 78 °C, followed by removal of the auxiliary by hydrolysis and decarboxylation of the Michael adducts, affords optically active -substituted <5-oxo esters232 (for a related synthesis of 1,5-diesters, see Section 1.5.2.4.2.2.1.). In the same manner, <5-oxo esters with contiguous quaternary and tertiary carbon centers with virtually complete induced (> 99%) and excellent simple diastereoselectivities (d.r. 93 7 to 99.5 0.5) may be obtained 233 234. 

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. 

Rates of deprotonation of a simple ketone (89) by lithium diisopropylamide (LDA) in THF at -78 °C show a first-order dependence on ketone, and an order of 0.58 ( 0.06) in base. Alternative pathways involving the LDA monomer and its solvent-complexed dimer (90) are considered. 

The loss of optical activity accompanying deprotonation of (/f)-2,2,6-trimethyl-cyclohexanone by lithium diisopropylamide (LDA, which exists as a dimer) in THF is governed by the rate equation v = /c [ketone] [LDA]°-, which is consistent with a rate-determining proton transfer involving amine monomer. ... 

Triethylamine in THF can be used as the external base to deprotonate triazolium salts. The resulting NHCs were complexed in situ, e.g., to [(/7 -cymene)RuCl2]2, [(/ -cod)RhCl]2, and [(/ -C5Me5)RhCl2]2. Sodium carbonate in water/ DMSO deprotonates imidazolium iodides in the presence of mercury(II) dichloride to give [Hg(NHC)2][Hgl3Cl]. " A pyridine-functionalized imidazolium salt was deprotonated by lithium diisopropylamide (LDA) in THF and attached in situ to [(p -cod)Pd(Me)Br] [Eq.(17)]. After abstraction of the bromide anion with silver(I) a tetranuclear ring is formed. 

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)" . 

To obtain complete conversion of ketones to enolates, it is necessary to use aprotic solvents so that solvent deprotonation does not compete with enolate formation. Stronger bases, such as amide anion ( NH2), the conjugate base of DMSO (sometimes referred to as the dimsyl anion),2 and triphenylmethyl anion, are capable of effecting essentially complete conversion of a ketone to its enolate. Lithium diisopropylamide (LDA), which is generated by addition of w-butyllithium to diisopropylamine, is widely used as a strong... 

Deprotonation of 3-picoline is more difficult (the anion cannot achieve stability through resonance, as happens with the others) and a much stronger base, LDA [lithium diisopropylamide (lithium propan-2-ylamide)], is needed. Once achieved, however, the conjugate anion behaves as a nucleophile and undergoes typical carbanion reactions (indeed, it is more reactive than its counterparts, since reactivity is most often the opposite of stability ). 

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... 

For the reaction of 1,3-dioxin -ones with electrophiles, activation by deprotonation of the side-chain alkyl group is required. Typically lithium diisopropylamide (LDA) is used as a base. The resulting lithium dienolates react with aldehydes <2002EJ0718> or with allyl bromides in the presence of Ar,Ar -dimethylpropyleneurea (DMPU) <2005AGE820, 2006CEJ2488> exclusively at the side-chain double bond, albeit in modest yields (Equation 25). 

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