Diisopropylamide anion

Another strong base routinely employed in synthetic procedures to prepare enolate anions is lithium diisopropylamide (LDA). The diisopropylamide anion is formed by removing a proton from... 

The diisopropylamide anion acts as a base and removes an acidic hydrogen from the carbon adjacent to the carbonyl group. The resulting enolate anion reacts as a nucleophile in an SN2 reaction, displacing the bromine at the primary carbon. 

The steric bulk of the diisopropylamide anion of LDA ensures that nucleophilic addition to the carbonyl carbon does not compete with deprotonation at the a-carbon. 

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). 

In addition to their behavior as bases, primary and secondary amines can also act as very weak acids because an N-H proton can be removed by a sufficiently strong base. We ve seen, for example, how diisopropylamine (pK-A 40) reacts with butyilithium to yield lithium diisopropylamide (LDA Section 22.5). Dialkylamine anions like LDA are extremely powerful bases that are often used... 

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]. 

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. 

A modification of the addition of (+ )-(/ )-4-methyl-l-(methylsulfinyl)benzenc to benzaldehyde was recently reported9. The sulfinyl anion is made with lithium diisopropylamide, transmeta-lated with zinc(II) chloride and then reacted with benzaldehyde. 

Formation of a-Sulfinyl Anions with Lithium Diisopropylamide and Subsequent Addition to a,/ -Unsaturatcd Ketones General Procedure1 ... 

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. 

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. 

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>. 

Lithium salts of resonance-stabilized organic anions have also found a role in carbon-phosphorus bond formation by displacement at phosphorus. The generation of the lithium salt derived from acetonitrile (or other aliphatic nitriles by reaction with butyl lithium or lithium diisopropylamide) provides for carbon-phosphorus bond formation by displacement of halide from phosphorus (Equation 4.24).68... 

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>. 

A stronger base and notably weaker nucleophile is the anion of hexamethyl-disilazane (Mc3Si)2NH, (34H). The anion, (34) , is electrogenerated ex situ, similarly to (33) , as its magnesium salt in dimethoxyethane with 15% v/v HMPA [75]. The PB (34H) is commercially available, relatively cheap, and in many respects behaves very much Kke lithium diisopropylamide (LDA). Substitution of HMPA with Ai-methyl-2-pyrrolidone was not successful [75]. 

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. 

Fig. 26 Chemical derivatization of PCL by an anionic route LDA lithium diisopropylamide...

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... 

Metallation of 3,4-dimethyl-l,2,5-thiadiazole (55) to the anion (56) was accomplished with the use of a nonnucleophilic base, lithium diisopropylamide <82JHC1247>. Nucleophilic attack at sulfur resulted in an alkyllithium reagent <70CJC2006>. The lithiomethyl derivative (56) was carboxylated to (57) with carbon dioxide and converted to the vinyl derivative (58) via an esterification, reduction, mesylation, and base elimination sequence (Scheme 12). 

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 ). 

N-Unsubstituted azomethine ylides may be generated thermally (79), and the N-metalated, 2-azaallyl anion versions may be generated by action of nonmetalhc bases such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) on certain imines (80). Although they are assumed to show similar chemical properties, these two species usually show different reaction patterns, as shown in Scheme 11.7, where the regio-and stereoselectivities of the cycloadditions are quite different (24,78-80). Metala-tion of (alkylideneamino)acetonitriles can be performed with metallic bases other than LDA. Thus, butyllithium, ethylmagnesium bromide, and magnesium bromide-diisopropylamide are also effective (78). The N-magnesioazomethine... 

A somewhat different approach to this series of compounds involves the reaction between a carbanion and an aromatic nitrile. Thus, a series of methylpyrazines 253 is first treated with lithium diisopropylamide (LDA) to generate an anion at the methyl group. Addition of an aromatic nitrile produces 254 (Equation 89) <2003JME222, 2004EUP1388541>. Many other examples have been reported <2003JME222>, including some with substituents at the open position in structure 254. 

Azaallyl anions, generated by treatment of arylmethylidene(arylmethylamines) with lithium diisopropylamide (LDA), react with 2-halogenopyridines to give a variety of substituted [l,7]naphthyridines (Scheme 47) <1995J(P1)2643>. 

This important synthetic problem has been satisfactorily solved with the introduction of lithium dialkylamide bases. Lithium diisopropylamide (LDA, Creger s base ) has already been mentioned for the a-alkylation of acids by means of their dianions1. This method has been further improved through the use of hexamethylphosphoric triamide (HMPA)2 and then extended to the a-alkylation of esters3. Generally, LDA became the most widely used base for the preparation of lactone enolates. In some cases lithium amides of other secondary amines like cyclo-hexylisopropylamine, diethylamine or hexamethyldisilazane have been used. The sodium or potassium salts of the latter have also been used but only as exceptions (vide infra). Other methods for the preparation of y-Iactone enolates. e.g., in a tetrahydrofuran solution of potassium, containing K anions and K+ cations complexed by 18-crown-6, and their alkylation have been successfully demonstrated (yields 80 95 %)4 but they probably cannot compete with the simplicity and proven reliability of the lithium amide method. 

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