Lithium diisopropylamide structure

A recent development in understanding the reactivity of bases has focused on their structures in solution and in the crystalline state. Due to the importance of dialkyl amide bases, there is a significant body of work, led by Williard and Collum , that has attempted to understand the structures of these reactive molecules. It is clear that they are aggregates. Lithium diisopropylamide (LiN/-Pr2) was isolated from a THF solution and X-ray crystallography revealed a dimeric structure (13 R = i-Pr, S = THF) in the... 

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). 

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. 

This transformation was first explored by treatment of l-bromo-4-(cyanomethyl)pentacyclo-[4.3.0.02 5.03-8.04-7]nonan-9-one ethylene acetal (61) with lithium diisopropylamide in tetrahy-drofuran at 0 °C, which resulted in almost quantitative yield of an inseparable mixture of two alkenes to which the structures l-bromo-4-cyanomethyltricyclo[4.2.1.02,5]nona-3,7-dien-9-one ethylene acetal (66) and l-bromo-4-(cyanomethylene)tricyclo[4.2.1.02,5]non-7-en-9-one ethylene acetal (67) were assigned.170,171 As illustrated below, the overall cage-degradation reaction can be mechanistically represented by the stepwise C —C bond fission reactions, whose driving force can be attributed to the apparently substantial reduction in cage constraint. 

Carboxylic acids can be alkylated in the a position by conversion of their salts to dianions [which actually have the enolate structures RCH=C(0 )21497] by treatment with a strong base such as lithium diisopropylamide.1498 The use of Li as the counterion is important, because it increases the solubility of the dianionic salt. The reaction has been applied1499 to primary alkyl, allylic, and benzylic halides, and to carboxylic acids of the form RCHjCOOH and RR"CHCOOH.1454 This method, which is an example of the alkylation of a dianion at its more nucleophilic position (see p. 368), is an alternative to the malonic ester synthesis (0-94) as a means of preparing carboxylic acids and has the advantage that acids of the form RR R"CCOOH can also be prepared. In a related reaction, methylated aromatic acids can be alkylated at the methyl group by a similar procedure.1500... 

The reactivity of 1,3-ditellurole has been inadequately investigated. Lithiation of the simplest 1,3-ditelluroles with lithium diisopropylamide (LDA) leads (depending on their structure) to either 2- or 4(5)-lithio derivatives (83TL237). Thus, 4-lithio-l, 3-ditellurole 57 is formed from 1,3-ditellurole, whereas lithiation of its 4-phenyl derivative produces 2-lithio-4-phenyl-l,3-ditellurole 58. The latter result is explained by the steric hindrance that the 4-phenyl substituent creates for the attack of LDA at position 5 of the five-membered ring. 

The a-protons of a ketone like propanone are only weakly acidic and so a powerful base (e.g. lithium diisopropylamide) is required to generate the enolate ion needed for the alkylation. An alternative method of preparing the same product by using a milder base is to start with ethyl acetoacetate (a [3-keto ester) (Fig.G). The a-protons in this structure are more acidic because they are flanked by two carbonyl groups. Thus, the enolate can be formed using a weaker base like sodium ethoxide. Once the... 

The direct metalation of 1,3-ditellurole (60 E = H) gave quite different results than the direct metalation of 4-phenyl-1,3-ditellurole (61 E = H) with lithium diisopropylamide (LDA) (83TL237). The parent system was lithiated at a vinylic position to give vinyl substituted products of structure (60) following electrophilic capture with benzaldehyde, methanol-O-d and methyl iodide. Identical results were obtained with 1,3-dithiole and 4-phenyl-l,3-dithiole with LDA. 

Alkylations of the Lithium Enolates. Treatment of the reagents with Lithium Diisopropylamide (LDA) generates the enolates (2) or ent- 2) (crystal structure of rac-TBDMS-(2) ) which can be alkylated to give, for instance, (/ )-a-methyl-dopa (3) or triacetyl (S)-a-methyl-dopa. ... 

Numerous instances have been described in the literature on the base-catalyzed isomerization of oxiranes with various structures. The product in the reaction of benzocycloalkene oxiranes with lithium diisopropylamide depends on the ring size it is either a transannular insertion product or a transannular product and some a-ketone or only a /3-ketone (Eq. 112). ... 

The structural chemistry and solution behavior of lithium diisopropylamide (LiN(CHMe2)2, EDA) typifies the complexities of these systems. Although the base-free compound crystallizes as infinite helical chains with two-coordinate lithium and four-coordinate nitrogen, it is isolated from A,A,A, A -tetramethylethylenediamine (TMEDA)/hexane mixtures as an infinite array of... 

The synthesis of (-)-Cio-desmethyl arteannuin B, a structural analog of the antimalarial artemisinin, was developed by D. Little et a. In their approach, the absolute stereochemistry was introduced early in the synthesis utilizing the Enders SAMP/RAMP hydrazone alkylation method. The sequence begins with the conversion of 3-methylcyclohexenone to the corresponding (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone. Deprotonation with lithium diisopropylamide, followed by alkylation in the presence of lithium chloride at -95 °C afforded the product as a single diastereomer. The SAMP chiral auxiliary was removed by ozonolysis. 

Synthesis of (—)-Lasubine II. A reductive desulfonylation with lithium in ammonia is employed in the total synthesis of quinolizidine alkaloid (—)-lasubine II.264 A conjugate addition of methyl (.S )-(2-pipcridyl)acetate to an acetylenic sulfone, followed by lithium diisopropylamide (LDA)-promoted intramolecular acylation is the key step in the preparation of the quinolizine structure of (—)-lasubine II (Eq. 154). 

The naturally occurring cryptand aplasmomycin (190) is one of a unique family of ionophore antibiotics, and several syntheses of the total structure, half structure and various abbreviated segments have been published. White et al. have now described a new approach to (190) which features a novel ring contraction based on the rearrangement of a-(acyloxy) acetates originally described by Chan et al. Thus, the key intermediate (191) was treated successively with lithium diisopropylamide and trimethylsilyl triflate leading to (192) which was ultimately converted to aplasmomycin. In Corey s recent... 

Ibrning to structurally more complex applications of 100, it has been shown that it can function as a Michael acceptor. For example, when the enolate of 2,4-dimethyl-cyclo-hexen-3-one (152) is treated with 100 in the presence of lithium hexamethyldisilazane (LiHMDS), dichlorovinylation takes place and 153 is formed. On the other hand, with lithium diisopropylamide (LDA) as base, the 1-chloroacetylene derivative 151 is produced [98-100] (Scheme 2-15). The reaction, which also takes place with other 1-chloroacetylenes, most likely involves the Michael intermediate 154 which — depending on reaction conditions — is either protonated or loses a chloride ion. On treatment with copper powder in tetrahydro-furan/acetic acid, 151 is dechlorinated the resulting terminal acetylene has been used for further transformations. 

The lithium diisopropylamide deprotonates the nitrogen, giving a resonance-stabilized anion. One of the resonant structures of this anion possesses a negative charge on a to a sulfone. 

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