Electrophilic reactions lithium compounds

Perfluoroacetylenic lithium compounds on reaction with electrophiles yield perfluoroacetylenic functional derivatives [78, 79] (equation 43)... 

Addition reactions of the a-seleno lithium reagent 26 to carbonyl compounds have been undertaken 27. The a-seleno lithium reagents are configurationally labile at — 78 °C 27 28 and, therefore, the diastereoselectivity observed with 26 ( 90 10) does not significantly depend on the nature of the electrophile but rather reflects the thermodynamic ratio of the diastereomeric lithium compounds. 

The only way to introduce two different electrophilic fragments in compounds such as 508 is to have a starting material with different halogens. This is the case with 510, which could be lithiated (bromide-lithium exchange) with t-butyllithium in THF at — 100°C giving intermediates 511, which reacted with a carbonyl compound R R CO and, after naphthalene-catalyzed lithiation, gave the new functionalized organolithium intermediate 512. Final reaction with 3-pentanone followed by hydrolysis yielded mixed products 513 (Scheme 142) °. 

The electrophilic reactivity of lithium carbenoids (reaction b) becomes evident from their reaction with alkyl lithium compounds. A, probably metal-supported, nucleophilic substitution occurs, and the leaving group X is replaced by the alkyl group R with inversion of the configuration . This reaction, typical of metal carbenoids, is not restricted to the vinylidene substitution pattern, but occurs in alkyl and cycloalkyl lithium carbenoids as well ". With respect to the a-heteroatom X, the carbenoid character is... 

A similar type of substitution, which clearly shows the electrophilic character, occurs in vinylidene carbenoids. In an early example of this reaction, Kobrich and AnsarP observed that the aUcene 70 results when the fi-configurated vinyl lithium compound 68 is treated with an excess of butyllithium and the fithioafkene 69 formed thereby is protonated (equation 41). Obviously, the nucleophilic attack of the butyl residue on the carbenoid takes place with inversion of the configuration. 

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... 

Evidence for this mechanism is (1) two equivalents of RLi are required (2) the hydrogen in the product comes from the water and not from the adjacent carbon, as shown by deuterium labeling 209 and (3) the intermediates 31-33 have been trapped.210 This reaction, when performed in tetramethylenediamine, can be a synthetically useful method211 of generating vinylic lithium compounds (33), which can be trapped by various electrophiles such as D20 (to give deuterated alkenes), C02 (to give a, 3-unsaturated carboxylic acids—6-34), or DMF (to give a, 3-unsaturated aldehydes—0-105). 

A similar electrophile, iodosyl triflate, CF3S020I0, was employed with arylsi-lanes [98]. The same reagent upon reaction with Me3SiCN formed (CN)2I+ TfO" which was coupled with tributyltin substituted arenes or heterocycles to afford bis(heteroaryl)iodonium triflates, e.g. dithienyl and difuryl derivatives [99]. However, this method gave poor results with nitrogen heterocycles. For them another approach was developed based on the reaction of the appropriate lithium compound with / -(dichloroiodo)chloroethylene (Scheme 33). Pyridine and quinoline compounds were formed in this way in moderate yield (23-71 %) [100]. 

Acyl anions (RC(=0)M) are unstable, and quickly dimerize at temperatures >-100 °C (Section 5.4.7). These intermediates are best generated by reaction of organolithium compounds or cuprates with carbon monoxide at -110 °C and should be trapped immediately by an electrophile [344—347]. Metalated formic acid esters (R0C(=0)M) have been generated as intermediates by treatment of alcoholates with carbon monoxide, and can either be protonated to yield formic acid esters, or left to rearrange to carboxylates (R0C(=0)M —> RC02M) (Scheme 5.38) [348]. Related intermediates are presumably also formed by treatment of alcohols with formamide acetals (Scheme 5.38) [349]. More stable than acyl lithium compounds are acyl silanes or transition metal acyl complexes, which can also be used to perform nucleophilic acylations [350],... 

Reduction of 2-chloro-l,3-diaza-2-silacyclopentanes with lithium metal in THF gives the corresponding lithium compound which was shown to be configurationally stable by NMR spectroscopy up to temperatures of 333 K in THF or 388 K in diglyme <20020M1319>. Reaction of the lithium compound with electrophiles can be used to functionalize the silaheterocycle at the silicon atom <20020M1319>. 

As a result of obtaining only one stereoisomer in the deprotonation stage of the two solvent systems, the aldehydes obtained after alkylation and hydrolysis are of opposite chirality. Consequently, it is possible to obtain an inversion of product chirality by a change in the reaction conditions, using the same chiral hydrazonic system. Nevertheless, the electrophilic substitution products are not obtained in equivalent enantiomeric excess, in spite of the high stereoselectivity in the deprotonation process, since the substitution process is so much less selective, i.e. the preference for electrophilic attack from one side of the lithium compound is not complete107. 

Sequential reaction of azines with alkyl hthium compounds and chloroformates usually affords the expected Reissert-type products 136, together with minor amounts of doubly acylated compounds 135 (Scheme 18b). Isoquinoline is likely to react directly with the alkyl-lithium compound to generate the alkylated lithio-enamine intermediate E, and this species may account for the formation of dihydroisoquinolines 135 and 136, through interaction with the electrophihc partner. Mamane recently expanded this concept by replacing the acylating agent with different electrophiles. These combinations lead exclusively to isomers 134 (Scheme 18) [118-120]. 

A common method for the preparation of carbene complexes without heteroatom substituents is the reaction of a coordinatively unsaturated metal complex with a diazoalkane. This method is effective for the preparation of CpOsCl(P Pr3)(=CHPh) from CpOsCl(PTr3)2. The carbene in this complex is electrophilic and reacts with aUcyl and aryl lithium compounds and with Grignard reagents see Grignard Reagents) (Scheme 14). ... 

The reaction is usually fast and is tolerant of most types of functional substituent, such as epoxy groups or unprotected carbonyl groups a variety of solvents can be used, most commonly THF at low temperature. Generally, when tin and hydrogen are present as competing electrophilic centres, alkyllithium compounds give transmetallation, whereas lithium diisopropylamide gives deprotonation (equation 22-2).7... 

To a solution of the ester (3-15 mmol) in THF (10-30 mL) was added t-BuLi (1.1 equiv) at —78°C. The solution was stirred under argon for 30 min (during this time, the lithium compound might precipitate), and the electrophile (1.2 equiv, dissolved in 2-5 mL of THF) was added. If the electrophile was a carbonyl compound, the reaction was quenched with aq NH Cl after 5 min, otherwise the solution was allowed to warm to rt over 4 h. The mixture was diluted with EtjO, washed with sat. aq NH4CI and brine, dried (MgS04.), concentrated, and purified by flash chromatography (pentane/EtjO),... 

Until about 30 years ago, hydrazones derived from carbonyl compounds were not used in organic synthesis. They were used only for analytical purposes , and as protecting groups of aldehydes and ketones ". Corey investigated dimethylhydrazones of ketones and aldehydes with a-hydrogens, and found that they undergo deprotonation with LDA or BuLi in THF at the a-carbons to the hydrazonic moiety in 90-100% yield. The formed lithium compounds, used as enolate anion equivalents, create new carbon-carbon bonds in their reaction with different electrophiles such as alkyl halides or oxiranes, ketones and aldehydes (equation 21). 

Direct metallation. Direct C-H metallations are of several types, of which the most important is reaction ( deprotonation ) with a strongly basic reagent, usually a lithium compound, but is also possible for magnesium and zinc. Electrophilic metallation can be carried out with palladium(II) and mercury(II) salts, and neutral C-H insertion by other transition metals is becoming increasingly important, usually for catalytic reactions. 

Whereas thioanisole, CH3SPh, is reported to give a mixture of ring-metallated and side-chain-metallated products upon interaction with butyllithium, the 0,S-acetal CH3OCH2SPh is lithiated only on the methylene carbon atom by BuLi in THF or sec-BuLi-TMEDA in THF [1-3]. Analogous metallations have been realized with 1,3-oxathiane [4]. The obtained lithium compounds have a limited thermal stability [5], so functionalizations with alkyl halides and epoxides, which are usually less fast than reactions with other electrophiles , give reduced yields. The 0,S-acetal PhSCH2OCH3 can be lithiated in a reasonable time with butyllithium in a THF-hexane mixture but the temperature has to be kept below — 40 °C to prevent decomposition of the lithiated intermediate into PhSLi and other (unidentified) products [5],... 

A similar situation is given in the meso-dicarbamate 192 [see Eq. (61)] [120]. The pro-S proton at the pro-R branch exhibits the highest reactivity in the (-)-sparteine-mediated deprotonation to form the lithium compound 193 with a small amount of the diastereomer 195. By applying prolonged reaction times (4-5 h), it is found that 195 is decomposed more rapidly than 193, leading to a further enrichment. Trapping of the reaction mixture by different electrophiles leads to essentially enantiomerically and diastereomerically pure products 194a-c. Allylation and benzylation result in lower diastereomeric ratios, probably due to SET mechanisms in the substitution step. 

The lithium compound 256 can react from two conformations 256a and 256b. In an a-substitution, products 258 or enf-258 are formed from both conformers, their ratio depends on the stereospecificity of the appropriate Sg reaction, which may occur with retention or inversion, depending on the electrophile. Electrophilic y-substitution of 256a and 256b can lead, depending on the stereospecificity of the substitution step, to four different stereoisomers with two pairs of enantiomers (257 and ent-257,259 and enf-259) 257 and enf-259 and as well, ent-257 and 259 can be regarded as pseudo-enantiomers . Since the latter pairs are diastereomers, in principle, these can be easily separated before deprotection. 

Hoffmann and coworkers proposed an excellent method for evaluating the configurational stability of the lithium carbanion within the time scale of the rate of the reaction with an electrophile (Hoffmann test) [12]. The Hoffmann test is composed of two experiments. In the first experiment, a racemic organo-lithium compound is reacted with a racemic aldehyde such as 2-(Nd -diben-zylamino)-3-phenylpropanal,the relative rate of formation of the diastereomeric products (k55 kjjj) being estimated by an antUsyn ratio of the products (Fig. 5). 

Lithium is also frequently used as alkyl lithium compounds. These are useful in substitution reactions for organic chemistry and have the unique capacity to invert the polarity of the functional carbon atom. Upon reduction, it s converted from an electrophilic species to a nucleophilic species. 

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