Lithium dialkylamide

Alkyllithium bases are generally less suitable for deprotofiation of compounds with strongly electron-withdrawing groups such as C=0, COOR and CsN. In these cases lithium dialkylamides, especially those with bulky groups (isopropyl, cyclohexyl), are the reagents of choice. They are very easily obtained from butyllithium and the dialkylamine in the desired solvent. 

Lithium dialkylamides are excellent bases for making ketone enolates as well Ketone enolates generated m this way can be alkylated with alkyl halides or as illus trated m the following equation treated with an aldehyde or a ketone... 

The deprotonation of the (1-oxopropyl) group of these compounds is achieved either by treatment with lithium dialkylamides or by the use of dialkylboron triflates in the presence of trialkylamines. In each case, exclusive generation of the corresponding (Z)-cnoiate results. 

A further improvement utilizes the compatibility of hindered lithium dialkylamides with TMSC1 at —78 °C. Deprotonation of ketones and esters with lithium dialkylamides in the presence of TMSC1 leads to enhanced selectivity (3) for the kinetically generated enolate. Lithium t-octyl-t-butyl-amide (4) appears to be superior to LDA for the regioselective generation of enolates and in the stereoselective formation of (E) enolates. 

To a solution of the lithium dialkylamide (1.1 mmol) in THF (2 ml) cooled to -78°C was added a solution to TMSC1 (5-10mmoI) in THF (2ml), also cooled to -78 °C. This was followed by dropwise addition of the carbonyl compound (lmmol) in THF (2ml). After lmin, triethylamine (2ml) was added, followed by quenching with saturated sodium hydrogen carbonate solution. The product was extracted into pentane, and these extracts were... 

Lithium bis(trimethylsilyl)cuprate, 29. 52 Lithium dialkylamides, 100 Lithium l-(dimethylamino)naphthalenide (LDMAN), 68,69,77 Lithium dimethylcopper, 131 Lithium hexamethyldisilazide, 73, 78 Lithium t-octyl-t-butylamide, 100 2.6-Lutidine, 93. 94... 

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. 

Kobayashi and co-workers have also reported an alternate synthesis of 1,4-disubstituted isoquinolines and a new synthesis of 1,3,4-dihydroisoquinoline derivatives <06BCJ 1126 06S2934>. The 1,4-disubstituted isoquinolines 121 are synthesized in good yields by reacting a variety of organolithiums 122 with different benzonitriles 123. In addition, a variety of lithium dialkylamides 124 were also reacted with different benzonitriles 123 to form 1 -amino-4-substituted isoquinolines 121 in moderate yields. 

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... 

Lithiation shifts obtained by comparison of 13C chemical shifts in lithium dialkylamides and the corresponding amines have been found to be quite substantial and decrease in the order a > p > 7 > 8 (439). 

Although modest, the results obtained with nonracemic lithium dialkylamides demonstrated the feasibility of such enantioselective transformations and important work has been undertaken from this date to improve both the yield and the ee values as well as developing a catalytic process. With this objective, both the use of homochiral lithium amide (HCLA) bases and organolithium-homochiral ligand complexes have been explored. This field has been extensively reviewed " and the following section presents a selection of the most outstanding results and recent developments. 

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... 

When 4-bromo- or 4-iododibenzofuran is treated with sodamide or a lithium dialkylamide, cine substitution occurs and the 3-amino derivative results. The 4,6-diiodo derivative similarly gives the 3,7-diamino compound. ... 

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... 

In liquid ammonia with alkali amides, or in Et20 or THF with lithium dialkylamides, these complications do not occur, because these bases are considerably weaker than BuLi. 

This process can be avoided if the solution of BuLi is cautiously added to a small excess of. vinylacetylene. Alkali amides or lithium dialkylamides do not cause such an oligomerization. 

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. 

The deprotonation of 5,6-dihydro-3-tnethyl-4//-l,2-oxazine with lithium dialkylamides or butyl-lithium as base proceeds with high regioselectivity at the 4-methylene protons due to the greater kinetic and thermodynamic acidity of these protons relative to the exocyclic methyl protons3. 

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. 

Thus far only compounds (A) and (B) yield ynamines when treated with either lithium alkyls or lithium dialkylamides, respectively. Thus far attempts to use compound (C) have led to other products [9]. Since little information has been published about compound (C), further research is required before it can be ruled out. 

As a dehydrohalogenating reagent, phenylmagnesium bromide is not so effective as are lithium dialkylamides, but in hexamethylphosphoramide it reacts with a,/9-dichloroenamines to give a 35% yield of the corresponding ynamine [18] (Eq. 23). 

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