Lithium reaction with electrophiles

Although less researched than the 2-position, modifications at the 6-position of intact penems have been reported. Generation of the dianion of the penem (52, R = CH ) using a strong base such as / -butyUithium or lithium diisopropylamide, followed by reaction with electrophiles yields 6-substituted 2-methylpenems in moderate yield (128). The enhanced acidity of the 6-proton in the bromopenem (88) [114409-16-4] h.a.s been exploited to prepare the... 

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

Stannyllithium compounds are important as sources of nucleophilic stannyl anions, and the dialkyltin lithium hydrides, R2SnLiH, have recently come to prominence as their reaction with electrophilic alkyl halides gives hydrides, R1R2SnH, with mixed alkyl groups (see Section 3.14.18.1).397... 

If the addition involves an alkynyllithium such as 34, the first-formed alkoxide intermediate 35 isomerizes into the propargylic-allenic lithium reagent. Reactions with electrophiles lead to either 36a or the allenol silyl ethers 36b (equation 13). ... 

Finally, the ring opening of substituted thioisocromans (402) with lithium and a catalytic amount of DTBB (5%) in THF at —78 °C gave the expected benzylic intermediates 403 which, after reaction with electrophiles at the same temperature and final hydrolysis with water, yielded functionalized thiols 404 (Scheme 113) . 

Whereas the halogen-lithium exchange is of limited importance for the generation of a-lithiated ethers, the reductive lithiation of 0/S-acetals has been applied more frequently, the versatility being enhanced by remarkable diastereoselective variants. Thus, a single diastereomer of the lithium carbenoid 52 results from the diastereomeric mixture 51 (equation 34) . Representative examples of a-lithiated ethers generated by this method and their reactions with electrophiles are given in Table 4. 

TABLE 5. Representative examples of a-lithiated ethers, generated by tin-lithium exchange, and reactions with electrophiles... 

After the optimization of the conditions for the production of o-bromophenyl-lithium to —78°C with a 0.8 s residence time, the scope was extended to sequential Br-Li exchange of both bromine substituents on the benzene ring and the reaction with electrophiles to form o-disubstituted benzene rings. This was done in a four-step reaction in one flow using four-linked microreactors (MRi ). For the second lithiation, the temperature of 0°C was sufficient, which was expected since the aryllithium intermediate is more stable than o-bromophenyllithium. 

As pointed out earlier (Sect. 7.1), alkyl lithium reagents induce metal-hydrogen exchange reactions. This possibility was investigated first by Paddock and coworkers [266,227]. They have found that the anion generated by the reaction of methylphosphazene with n-butyl lithium interacts with electrophiles such... 

The enolates of fluoroacetate or fluorothioacetate esters are generated either through deprotonation with a lithium amide or by an in situ reduction of ethyl bromofluoroacetate with zinc. These enolates can undergo diverse reactions with electrophiles (Figure 2.7) ... 

A behavior similar to that of pyridine and pyrazine N-oxides is exhibited by complexes of pyridines with hexafluoroacetone. Such complexes are expected to enhance the acidity of the pyridine hydrogens by oxygen-lithium chelating effects and therefore direct 2-deprotonation. In fact, treatment of f-butylpyridine (495) with LiTMP/THF-Et20/- 107°C generated, via the known complex 507, the stable 2-lithio species 508 which, upon reaction with electrophiles, furnished 2-substituted pyridines 509 (Scheme 154) (83JOC4156). 

Lithiation of dihydrodinaphthothiepine 23 with 2.2 equiv of lithium naphthalenide in THF at —78 °C followed by reaction with electrophiles at — 78 °C led, after hydrolysis, to the unsymmetrically 2,2 -disubstituted binaphthyl 132 in 36-64% yields (Equation 16). Using milder reduction conditions, the first lithiation product 128 reacted with the electrophile giving an intermediate of type 131, which by hydrolysis afforded thiols 132. 

The reactions of ketone dilithio ,/i-dianions with imines and hydrazones have been investigated.77 The nucleophilic addition reaction to C—N double bonds took place selectively at the -position of dianions to form lithium (Z)-enolates containing a lithium amide portion, which is then transformed into y-amino ketones and related compounds by the subsequent reaction with electrophiles. 

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>. 

Desymmetrisation by enantioselective ortholithiation has been achieved with ferrocenylcarboxamides 434,187 and also (with chiral lithium amide bases) a number of chromium-arene complexes.188 The chromium arene complex 435, on treatment with s-BuLi-(-)-sparteine, gives 436 enantioselectively, and reaction with electrophiles leads to 437. However, further treatment with r-BuLi generates the doubly lithiated species 438, in which the new organolithium centre is more reactive than the old, which still carries the (-)-sparteine ligand. Reaction of 438 with an electrophile followed by protonation therefore gives ent-431.m... 

The simplest member of the series, the 2,4-pentadienyl metallo species, has been shown by NMR studies,132 133 to adopt either a W-shape or a U-shape conformation with the metal being lithium or potassium, respectively, when both are dissolved in tetrahydrofuran.134 136 The W-form is adopted by the 2,4-pentadienylpotassium when the organometallic species is generated in liquid ammonia137 or in paraffinic suspension.138 This has also been confirmed by the stereochemistry of the products formed after reaction with electrophiles.134,135,138,139... 

Lithium halocarbenoids are no more subject of mechanistic interest only. Improvement of preparative techniques in the last ten years made them to valuable synthetic intermediates which are stable in the temperature range between —130 and —70 °C. They are generated from readily available starting materials and give high yields of adducts on reaction with electrophiles. 

An extension of the synthetic applicability of lithium halomethanes is achieved by the simultanous presence of another main group heteroatom at the same carbon. Thus, if one of the chlorine atoms of dichloromethyllithium is replaced by a sulfonylamin group, the following products are obtained by reaction with electrophiles (Eq. (23)) 25). The substituted carbenoid can be converted to normal carbonyl adducts as well as to olefins and cyclopropanes. 

The formation of ring systems by the anionic cyclization of olefinic alkyl, aryl and vinyl-lithiums is an interesting synthetic transformation that provides a regiospecific and highly stereoselective route to five-membered carbocycles and heterocycles99. Most importantly, it is possible to functionalize the initially formed cyclization product by a tandem reaction with electrophiles, a reaction that is not generally possible in the case of radical cyclizations. 

When (Z)-6-chloro-l-phenylhex-l-ene 200 was lithiated under DTBB catalysis, the cyclized product 202 was always obtained either at —78 or at —30 °C. After the first chlorine-lithium exchange a carbolithiation took place to yield the intermediate 201, which by reaction with electrophiles, E, and final hydrolysis gave products 202 (Scheme 60). At —78 °C the reaction under Barbier-type conditions did not work. Also in this case, the corresponding reduced product (202 with E = H) was the main by-product detected. 

Lactols and their acetals can be transformed easily into their 2-arylsulfonyl derivatives 337 by reaction with a sulfinic acid under Lewis acid activation. The corresponding organolithiums are prepared by deprotonation with n-BuLi or LDA and, after reaction with electrophiles, a /(-elimination of sulfinic acid afforded a cyclic a-substituted enol ether514,547,548. 2-Lithio-2-(arylsulfonyl)tetrahydropyrans equilibrated to give mainly the anomer with the lithium atom at the equatorial position549. 

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