Lithium dialkylamides reactions

Ketone p-toluenesulfonylhydrazones are converted to alkenes on treatment with strong bases such as an alkyllithium or lithium dialkylamide.286 Known as the Shapiro reaction,2 7 this proceeds through the anion of a vinyldiimide, which decomposes to a vinyllithium reagent. Treatment of this intermediate with a proton source gives the alkene. 

Hindered lithium dialkylamides can generate aryl-substituted carbenes from benzyl halides.162 Reaction of a,a-dichlorotoluene or a,a-dibromotoluene with potassium r-butoxide in the presence of 18-crown-6 generates the corresponding a-halophenylcarbene.163 The relative reactivity data for carbenes generated under these latter conditions suggest that they are free. The potassium cation would be expected to be strongly solvated by the crown ether and it is evidently not involved in the carbene-generating step. 

Dialkylamino derivatives of elements located in the periodic table to the left or below those listed above cannot be prepared by the above method due to either the ionic character of some of the inorganic halides or the formation of stable metal halide-amine addition products. Therefore, other methods must be applied. Dialkylamino derivatives of tin7 and antimony8 are conveniently obtained by reaction of the corresponding halides with lithium dialkylamides. Others, such as the dialkylamino derivatives of aluminum,9 are made by the interaction of the hydride with dialkylamines. Dialkylamino derivatives of beryllium10 or lithium11 result from the reaction of the respective alkyl derivative with a dialkylamine. 

Ketone p-toluenesulphonyl hydrazones can be converted to alkenes on treatment with strong bases such as alkyl lithium or lithium dialkylamides. This reaction is known as the Shapiro reaction68. When w./i-LinsaUi rated ketones are the substrates, the products are dienes. This reaction is generally applied to the generation of dienes in cyclic systems where stereochemistry of the double bond is fixed. A few examples where dienes have been generated by the Shapiro reaction have been gathered in Table 669. 

A second major reaction of oxaspiropentanes as reactive epoxides is their elimination to form vinylcyclopropanols 29,49,62). A rapid elimination to vinylcyclo-propanols occurs when the oxaspiropentanes are exposed to lithium dialkylamides in hexane or pentane as exemplified in Eq. 34 and Table 4. 

Kinetic enolates. Alkyllithium reagents have the advantage over lithium amides for deprotonation of ketones in that the co-product is a neutral alkane rather than an amine. This bulky lithium reagent is useful for selective abstraction of the less-hindered a-proton of ketones with generation of the less-stable enolate, as shown previously for a hindered lithium dialkylamide (LOBA,12,285). Thus reaction of benzyl methyl ketone (2) with 1 and ClSifCH,), at - 50° results mainly in the less-stable enolate (3), even though the benzylic protons are much more acidic than those of the methyl group, the less hindered ones. Mesityllithium shows... 

Phenyl-dibenzophosphole (164) results from the reaction of tetraphenyl-phosphonium chloride with certain lithium dialkylamides a free-radical mechanism... 

Strongly basic reagents, such as lithium dialkylamides, are required to promote the reaction. The stereochemistry of the ring opening has been investigated by deuterium labeling. A proton cis to the epoxide ring is selectively removed.115... 

The same authors later reported that although sterically hindered lithium dialkylamides do not react under the normal conditions, they do undergo an unusual 1,6-addition to the oxazolinylnaphthalene 511 in the presence of excess HMPA (8-10 equiv)." ° These reactions are also diastereoselective to afford the trans tandem adduct as the major product (Scheme 8.166). A dimeric lithium... 

Acetylenic ethers react with lithium dialkylamides to give ynamines in good yields [13] (Eq. 13). Examples of this reaction are described in Table II. 

The 1-alkynyl (0.55 mole) is added in 5 min to a solution of 0.50 mole of lithium dialkylamide in 500 ml of ether at room temperature. The ether is removed by distillation and an exothermic reaction starts at a bath temperature of about 80°C. Heating is continued for an additional 30 min at 110°-120°C and then the reaction products are distilled at 15 mm Hg pressure using a short Vigreux column. The heating bath is raised to 170°C and the last traces of products are removed by distillation at 1 mm Hg pressure. In all cases the distillation receiver should be cooled to —80°C. The entire distillates are combined and fractionated through a 30 cm Widmer column. Some typical results of using this method are shown in Table II. 

General Method for Preparation of Ynamines by Reaction of Acetylenic Ethers with Lithium Dialkylamides [13]... 

Lithium dialkylamide. Four catalysts, namely lithium dimethylamide, lithium diethylamide, lithium di-n-butylamide and lithium di-i-propylamide, have been prepared by the reaction of ji-butyllithium and the corresponding amines. Characterization of these amides was performed by G.C.-Mass Spectroscopy after D O quenching of the amides. Further analysis for the total alkalinity was performed by a titration... 

Kauffmann showed that treatment of halopyridines 34 with an excess of lithium dialkylamides at room temperature leads, via the intermediate 3,4-pyridyne (35), to an isomeric mixture of the amide addition products 36 and 37 (Scheme 11) [71AG(E)20]. Such reactions are inconsequential if they are performed at low temperatures where the rate of lithium halide elimination is slow. 

This rearrangement can be used to effect the equivalent of the Amdt-F.istert synthesis4 by reaction of an ester with dibromomethyllithium (5, 403 6, 162-163) in the presence of a lithium dialkylamide and then with r-butyllithium (equation I). 

This reaction type, known as directed ortho metalation reaction, requires strong bases, normally an alkyllithium reagent (most lithium dialkylamides are of insufficient kinetic basicity). Alkyllithium bases show high solubility in organic solvents due to association into aggregates of defined structure, typically as hexamers in hydrocarbon solvents e. g. hexane or tetramers-dimers in polar solvents e. g. THF (see Chapter 5). 

Chen, J. Cunico, R. F. a-Aminoamides from a carbamoylsilane and aldehyde imines. Tetrahedron Lett. 2003, 44, 8025-8027. Viruela-Martin, P. Viruela-Martin, R. Tomas, F. Nudelman, N. S. Theoretical studies of chemical interactions. Ab initio calculations on lithium dialkylamides and their carbonylation reactions. J. Am. Chem. Soc. 1994, 3 36, 10110-10116. 

The relative power of DMG (Table 1), established by experiments at low temperature and short reaction times and thus crudely representative of kinetic control conditions, may vary with inter- and intramolecular competition, conditions, and sometimes results are conflicting. Nevertheless, for synthetic practice this hierarchy follows a qualitative order consistent with CIPE and serves as a useful predictive chart. For thermodynamic control conditions, the pchart of Fraser of 12 DMG [27], determined by equilibrium deprotonation using LiTMP (pka=37.8), is a guide for lithium dialkylamide DoM reactions. 

Eliminations of epoxides lead to allyl alcohols. For this reaction to take place, the strongly basic bulky lithium dialkylamides LDA (lithium diisopropylamide), LTMP (lithium tetramethylpiperidide) or LiHMDS (lithium hexamethyldisilazide) shown in Figure 4.18 are used. As for the amidine bases shown in Figure 4.17, the hulkiness of these amides guarantees that they are nonnucleophilic. They react, for example, with epoxides in chemoselective E2 reactions even when the epoxide contains a primary C atom that easily reacts with nucleophiles (see, e.g., Figure 4.18). 

Aziridine —> P-lactam.1 This transformation can be effected by insertion of CO into the N-C bond of an aziridine. Thus reaction of N-benzyl-2-methylaziridine (1) with lithium iodide in refluxing THF provides a lithium dialkylamide (a) that reacts with Ni(CO)4 to form the p-lactam 2 in 51% yield. Both reactions probably... 

The direction of ring-opening of 5,10-epoxy-9(ll)-enes by bases depends upon the reaction conditions.235 Thus the a-epoxide (288) loses a proton from C-12 with potassium t-butoxide to give the 5a-hydroxy-9,11-diene (289), but lithium dial-kylamides favour formation of the 10a-hydroxy-4,9(1 l)-diene (290). These and related results suggest that the lithium dialkylamides are poorly dissociated, and favour a 1,2- rather than a 1,4-epoxide-opening reaction.235... 

Among the methods for their preparations, two reactions described by House have been employed widely 7 a thermodynamically controlled sil-ylation with chlorotrimethylsilane/triethylamine in hot dimethylformam-ide or a kinetically controlled reaction which involves lithiation with a lithium dialkylamide followed by quenching with the chlorosilane. Each method has its own merits and drawbacks with respect to three important factors regio-, stereo-, and chemoselectivities. 

Diaslereoselective Mannich reaction. Mannich bases can be prepared by addition of a lithium dialkylamide to a nonenolizable aldehyde to form a lithium alkoxide. Trans-metallation provides a trichlorotitanium alkoxide, which reacts with a lithium enolate to form a Mannich base. 

---