Naphthalenes lithiation

In 1-methoxy naphthalene, lithiation occurs predominantly at 2-position. This is because the hydrogen at this position is more acidic than that at 8-position. The greater acidity for the 2-H is due to the presence of an oxygen atom at the closer 1-position. 

In 2-methoxy naphthalene lithiation occurs, to larger extent, at 3-position than at 1-position This is unexpected. Both the positions are ortho to the OCHj group. The acidity of 1-H is expected to be more because ofthe presence of 1,2-doubIe bond in naphthalene (this structure is more important than the one with 2,3-double bond). 

This ligand has also been used by the same authors to promote the addition of ZnMe2 to a functionalised a,(3-unsaturated ketone in the asymmetric key step of the first enantioselective synthesis of (-)-frontalin. This synthesis started with the naphthalene-catalysed lithiation of a chlorinated ketal (Scheme 4.15) that, after several transmetalation processes, was trapped by reaction... 

Of particular note here is that, besides the organolithium derivative, the solvent also plays an important role [191] Me20 was found to be a highly effective for the in-situ production of the radical anion 2-354 from its precursor N,N-dimethylammo naphthalene. For the reductive lithiation of the thioethers and the following steps, the addition of pre-cooled Et20 combined with subsequent removal of the Me20 under reduced pressure gave the best results. 

The dynamic behavior of various solid organolithium complexes with TMEDA was investigated by variable-temperature and CP/MAS and Li MAS NMR spectroscopies. Detailed analysis of the spectra of the complexes led to proposals of various dynamic processes, such as inversion of the five-membered TMEDA-Li rings and complete rotation of the TMEDA ligands in their complex with the PhLi dimer (81), fast rotation of the ligands in the complex with cyclopentadienyllithium (82) and 180° ring flips in the complex with dilithium naphthalene (83) °. The significance of the structure of lithium naphthalene, dilithium naphthalene and their TMEDA solvation coiMlexes, in the function of naphthalene as catalyst for lithiation reactions, was discussed . ... 

Since different reactivity is observed for both the stoichiometric and the catalytic version of the arene-promoted lithiation, different species should be involved in the electron-transfer process from the metal to the organic substrate. It has been well-established that in the case of the stoichiometric version an arene-radical anion [lithium naph-thalenide (LiCioHg) or lithium di-ferf-butylbiphenylide (LiDTBB) for using naphthalene or 4,4 -di-ferf-butylbiphenyl (DTBB) as arenes, respectively] is responsible for the reduction of the substrate, for instance for the transformation of an alkyl halide into an alkyllithium . For the catalytic process, using naphthalene as the arene, an arene-dianion 2 has been proposed which is formed by overreduction of the corresponding radical-anion 1 (Scheme 1). Actually, the dianionic species 2 has been prepared by a completely different approach, namely by double deprotonation of 1,4-dihydronaphthalene, and its X-ray structure determined as its complex with two molecules of N,N,N N tetramethylethylenediamine (TMEDA). ... 

Although the lithiation of chlorobenzene did not occur in THF at —78 °C after 4 h, the addition of a catalytic amonnt of naphthalene (3%) allows this transformation after 45 min under the same reaction conditions . 

Allylic and benzylic ethers can also be cleaved using an arene-catalyzed lithiation, so the corresponding organohthium intermediates could be generated. Thus, different benzylic ethers 49 were hthiated using a catalytic amount of naphthalene (5%) to yield the expected intermediates 50, which after reaction with electrophiles and final hydrolysis gave products 51 (Scheme 16) . ... 

Nonenolizable benzylic carboxylates, such as pivalates 55, were lithiated in the presence of a catalytic amount of naphthalene (10%) and the electrophile, to yield, after hydrolysis, the expected products 20. The application of the same reaction to different ally lie or benzylic carbonates 56 yielded the same type of products 20 (Scheme 18) °. 

Another possibility of transforming indirectly alcohols into alkyllithium compounds consists in nsing the corresponding sulfates. Alkyl sulfates 60 were lithiated using naphthalene (4%) as the electron carrier catalyst in THF at —78 °C yielding two equivalents of the corresponding alkyllithinm 61. Further addition of an electrophile at —78 to 0°C led to the formation, after hydrolysis, of the final prodncts 20 (Scheme 22) ... 

The naphthalene-catalyzed (10%) lithiation of iV-allylic or iV-benzylic pivalamides 66 in the presence of an electrophile at —78 or 0 °C, respectively, gave, after hydrolysis, the expected products 20 (Scheme 25) °. 

The reaction shown in Scheme 25 has been successfully used to deprotect Al-benzylic carboxamides using water as the quenching reagent, after the naphthalene-catalyzed lithiation . 

An alternative to the use of pivalamides 66 is the lithiation of triflamides 67 catalyzed by naphthalene (4%) in the presence of different electrophiles at temperatures ranging between —78 and 0 °C, so after hydrolysis the expected products 20 were isolated (Scheme 26). ... 

The application of the naphthalene-catalyzed (10%) lithiation to benzylic ureas 69 under Barbier-type conditions in THF at —78 or — 30°C led to the formation of the expected products 35, after hydrolysis (Scheme 28) °. 

The naphthalene-catalyzed (8%) lithiation of phenyl sulfones 80 under Barbier conditions in THF at temperatures ranging between —78 and 20 °C led, after hydrolysis, to the formation of the corresponding products 20 (Scheme 33). ... 

The naphthalene-catalyzed (3%) lithiation of carbamoyl or thiocarbamoyl chlorides 91 in the presence of carbonyl componnds or imines as electrophiles in THF at temperatnres ranging between —78 to 20 °C led to the expected fnnctionalized amides or thioamides 92 after hydrolysis (Scheme 39) . ... 

Another type of acyllithium synthons was generated in situ from chloroimines. The naphthalene-catalyzed (4%) lithiation of chloroimines 93 in THF at —78 °C was followed by filtration of the excess of lithium, being then treated with an electrophile and finally hydrolyzed, to yield functionalized imines 94 (Scheme 40) . ... 

A naphthalene-catalyzed (<10%) lithiation of a,a-dibromo esters 152 in THF at —78°C was used to generate ester dianions 153, which by warming at 0°C gave lithium ynolates 154. These intermediates were trapped by carbonyl compounds, for instance benzophenone, to give, after final hydrolysis with water, a,/3-unsaturated acids 155 (Scheme 55)" ... 

The y-chloro alcohol 160 was lithiated, after deprotonation with a n-butyllithium in THF at —78°C, using lithium and a catalytic amount of naphthalene (1%) at the same temperature to give the corresponding intermediate 161, which was quenched with water, yielding 1-phenylpropanol (162) (Scheme 57). ... 

The lithiation of y-chloro acetal 175 with lithium and a catalytic amount of naphthalene (4%) allowed the preparation of the intermediate 176, which can be considered as a masked lithium homoenolate, and was used for the preparation of the hydroxy ketone 179 through the hydroxy acetal 177 and dithiane 178 using known chemistry (Scheme 62)" . 

Naphthalene-catalyzed (5%) lithiation of the chlorinated thioether 203 in the presence of pivalaldehyde gave, after hydrolysis, the product 204 in which, together with the... 

Naphthalene-catalyzed (5%) lithiation of the diiodinated ketal 205 afforded directly the cyclobutane derivative 206, a i5-iodinated organoUthium compound probably being involved (Scheme 71). In this case, a 5-elimination of lithium iodide is preferred to a y- or 5-elimination of lithium aUcoxide. 

Chlorinated ketals 221 were lithiated using a catalytic amount (8%) of naphthalene in THE at —78°C to generate the corresponding masked lithium 5-enolates 222, which upon treatment with different electrophiles in THE at temperatures ranging between —78 and 20 °C, and final hydrolysis with water, afforded protected functionalized ketals 223 (Scheme 76). The application of this methodology to the chlorinated dithiane 224, under the same reaction conditions, gave the intermediate 225 and finally products 226 (Scheme 76) -... 

The naphthalene-catalyzed (3-12%) lithiation of deprotonated chloro phenols and anilides 236 performed with n-butylUthium in THF at 0 or —78 °C, respectively, gave the corresponding functionalized aryllithium intermediates 237 which, by reaction with electrophiles and final hydrolysis, yielded the corresponding polyfunctionalized molecules 238 (Scheme 79) . 

An interesting case of different regiochemistry in the ring opening of an epoxide using a substoichiometric amount (60%) of naphthalene in the lithiation process was observed with epoxides 282. After the naphthalene-promoted lithiation process the most unstable... 

Tetrahydrofuran itself can be opened using either the stoichiometric or the catalytic version of arene-promoted lithiation, but both cases need the activation by boron trifluoride. The catalytic reaction was performed by treating the solvent THF 324 with the complex boron trifluoride-etherate and a catalytic amount (4%) of naphthalene. The intermediate 325 was formed. Further reaction with carbonyl compounds and flnal hydrolysis yielded the expected 1,5-diols 326 (Scheme 95), which could be easily cyclized to the corresponding substituted tetrahydropyrans under acidic conditions (concentrated FlCl). 

The naphthalene-catalyzed (2.5%) lithiation of phthalan 330 (or its substituted derivatives ) in THF at room temperature allowed the preparation of the functionalized benzyllithium intermediate 331, which reacted with electrophiles at —78°C to give, after hydrolysis, the corresponding functionalized benzyl alcohols 332 (Scheme 97). When carbon dioxide was used as the electrophilic reagent, the corresponding 5-lactone was directly obtained . When carbonyl compounds were used as electrophiles, the cyclization of the resulting products 332 under acidic conditions (85% H3PO4) allows the synthesis of substituted isochromans. 

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