Lithiation, DTBB-catalyzed

In the case of unsaturated chloramines 209, the DTBB-catalyzed lithiation had to be carried out in the presence of the electrophile in THF at —78 °C in order to avoid decomposition of the corresponding functionalized organolithium intermediate through elimination reactions. Final hydrolysis yielded a mixture (variable ratios 11.5/1 to 1/19 depending on the electrophile) of the a- and y-products 210 (Scheme 72) . ... 

Functionalized propargyUc organolithium compounds are probably involved in the transformation of chlorinated ethers or amines 211 into polyfunctionalized products 212, which were achieved through a DTBB-catalyzed lithiation under Barbier-type reaction conditions (Scheme 73). The reaction failed for the corresponding thioethers (Y =... 

A useful application of the chemistry shown in Scheme 83 is the synthesis of branched-chain functionalized carbohydrates. For this purpose two epoxides 261 and 262 derived from D-glucose and 263 derived from D-fructose were prepared following reported methodologies, and were submitted to a DTBB-catalyzed lithiation as described above in Scheme 83. The expected intermediates 264-266 and final products 267-269 were prepared in a regio- and stereoselective manner in 15- 95% yield" Also here, the use of a prochiral electrophile gave equimolecular amounts of both diastereomers. 

An unexpected result was obtained when DTBB-catalyzed lithiation was applied to the vinyl-oxetane 313 . After work-up, lactone 314 was isolated, the process being explained by an elimination reaction via a radical pathway more than by reduction of the benzyl radical into the anion. Thus, this hypothetical intennediate reacted with the lithium enolate of acetaldehyde, generated in situ by reductive decomposition of THF (Scheme 92). 

From a mechanistic point of view, 9-snbstitnted xanthenols 586 (prepared from the dianion of xanthen-9-one 585 in situ generated by a DTBB-catalyzed lithiation in THF, and different alkyl halides in 31-93% yield) are of interest due to rearrangements, which occurred under acidic conditions . ... 

MCPBA in dichloromethane (DCM) continues to be used as an oxidant for the preparation of benzo-l,5-dioxapins <2001S473, 1996SC4459>. Dibenzothiins and phenoxathiins undergo DTBB-catalyzed lithiation (DTBB - 4,4 -di-fert-butylbiphenyl). Reaction of the so-formed lithio intermediates with suitable electrophiles gives 29, which undergoes cyclization (Scheme 12) <2002CL726>. 

For 6-chloro-2-phenylhex-l-ene, 197, the DTBB-catalyzed lithiation, even at — 78 °C, gives the cyclic intermediate 198 (probably formed by an intramolecular carbolithiation), which by reaction with some electrophiles afforded, after hydrolysis, the corresponding products 199 (Scheme 59). The conversion is total after about 1 h the rest of the starting material is transformed into a mixture of compounds, among them the reduced product... 

The DTBB-catalyzed lithiation of 4-hetero-substituted dibenzothiins (68), such as phenoxathiin (68a), phenothiazine (68b) and thianthrene (68c), at low temperature gives the corresponding functionalized organolithium intermediates (69), which by reaction with different electrophiles afford, after hydrolysis, the expected functionalized... 

However, conversion with other electrophiles may require a transmetallation reaction such as the lithium-copper or lithium-boron exchange. For instance, when the cyclopentylmethyllithium 158 generated by 4,4 -di-tert-butylbiphenyl (DTBB)-catalyzed lithiation of 6-chlorohex-l-ene in THF was treated with an equimolecular amount of the complex CuCN-2LiCl, the organocopper intermediate 159 was formed (Scheme 10.52) [45], and this does react with a large variety of alkyl and propargyl electrophiles to give adducts 160-163 after hydrolysis. 

Vinyllithium acetals 133, compounds of type IX, were prepared from the corresponding chlorinated precursor 132 by a DTBB-catalyzed lithiation at low temperature. They reacted with electrophiles to give compounds 134. In the case of using chiral starting materials (132, R = Me), the reaction with prostereogenic carbonyl compounds took place with almost null stereoselectivity (Scheme 2.18) [111]. 

A similar situation takes place when an unsaturated chlorinated ketal is used as starting material. When the /S-chloro unsaturated ketal 140 (R = H) was submitted to a DTBB-catalyzed (5%) lithiation in THF at —78 °C, the corresponding lithium intermediate 141 was generated, which after reaction with different electrophiles at the same temperature gave, after hydrolysis, the expected products 142 (Scheme 52)"". ... 

Lithium homoenolates derived from carboxylic acids were generated from the corresponding /3-chloro acids by means of an arene-catalyzed lithiation. Chloro acids 186 were deprotonated with n-butyllithium and lithiated in situ with lithium and a catalytic amount of DTBB (5%) in the presence of different carbonyl compounds to yield, after hydrolysis, the expected hydroxy acids (187). Since the purification of these products is difficult, they were cyclized without isolation upon treatment with p-toluenesulfonic acid (PTSA) under benzene reflux, into substituted y-lactones 188 (Scheme 64) . 

By a DTBB-catalyzed (5%) lithiation of chlorinated unsaturated amines 191 in the presence of a carbonyl compound as electrophile, the final hydrolysis afforded 192 as a Z/E mixture of diastereomers (Scheme 66). In this process, the corresponding sp -hybridized functionalized organolithium intermediate is probably involved. 

A particular case for the generation of a y-substimted organolithium compound, derived from an imine, was used for the synthesis of 2-substituted pyrrolidines. DTBB-catalyzed (5%) lithiation of y-chloro imines 196 yielded, after hydrolysis, 2-substituted pyrrolidines 198, including nomicotine (R = H, R = 3-pyridyl). The corresponding y-nitrogenated organolithium intermediate 197 was probably involved (Scheme 68). ... 

The preparation of functionalized aryllithium compounds bearing an oxygen- or sulfur-containing functionality in a benzylic position is also possible by arene-catalyzed lithiation. When chlorinated materials 239 were deprotonated (for Y = OH, SH) with n-butyllithium in THF at —78 °C and then lithiated using DTBB as the catalyst at the same temperature. 

The same process shown in Scheme 88 starting from different 2-substituted oxetanes and using biphenyl as the electron-carrier catalyst under THF reflux has been used to prepare regioselectively substituted primary alcohols. On the other hand, the combination of a DTBB-catalyzed ca 20%) lithiation with triethylaluminium in TFIF at —78 °C has been used for the transformation of strained oxetanes to substituted di- and triquinanes through a rearrangement process . An example is given in Scheme 89 for the transformation of oxetane 299 into the product 302 through radicals 300 and 301. 

A chiral version of the above-mentioned ring opening of oxetanes has been applied to chiral oxetanes. An example is shown in Scheme 90 starting from oxetane 303, which after DTBB-catalyzed (5%) lithiation in TFIF at 0°C gave the (/-functionalized organohthium intermediate 304, which by treatment with different electrophiles and final hydrolysis with water yielded the corresponding products 305 (Scheme 90) °. 

Concerning the arene-catalyzed lithiation of 4-77-chromene 386, the process is not of synthetic interest as compared to the same process applied to 2,3-benzofuran 348 because both alkyl-and aryl-oxygen cleavage took place using DTBB (5%) as the electron-carrier... 

Dioxanes can be opened by an arene-catalyzed lithiation only if the carbon-oxygen bond to be cleaved occupies an allylic or benzylic position. This is the case of the vinyl-dioxane 416, which reacted with lithium and a catalytic amount of DTBB in THE at 0 °C, and the allylic intermediate 417 generated reacted at the y -position with tridecyl iodide to yield the compound 418, used in the synthesis of plasmenyl-type lipids (Scheme 117) . 

DTBB-catalyzed (5%) lithiation of any of the dichlorobutenes 480-482 in the presence of an electrophile in THE at 0 °C gave, after hydrolysis, the same isomeric mixture of 1,2- and 1,4-products (483 and 484, respectively), independently of the structure of the starting material (Scheme 135). Unexpectedly, the (Z)-isomer was the major one for products 484. The result obtained in this reaction indicates that the mechanistic pathway should be the same in the three cases. 

DTBB-catalyzed (2.5%) lithiation of phthalan (330) (see also Section VI.C.l) was performed in a sequential fashion. After the first lithiation at room temperature the first electrophile was reacted at —78 °C, giving 487 as intermediates. After allowing the temperature to rise to 20 °C, a second lithiation took place giving the new intermediates 488, which finally were treated with a second electrophile giving, after hydrolysis, the difunctionalized products 489 (Scheme 137) . 

Simple enamines cannot be deprotonated directly at the a-position due to their low acidity, but starting from a-chloroenamines 685, a-lithioenamines 686991 have been prepared by chlorine-lithium exchange using an arene-catalyzed lithiation992. The treatment of compounds 685 with an excess of lithium and a catalytic amount of 4,4 -di-tert-butylbiphenyl (DTBB) in THF at —90 °C allowed the preparation of intermediates 686, which were trapped with a variety of electrophiles (Scheme 177). For aldol reactions, the arene-catalyzed lithiation has to be performed in the presence of aldehydes (Barbier conditions) at —40 °C. These adducts were transformed into a-hydroxy ketones after acid hydrolysis with hydrochloric acid or silica gel. 

Cyclic alkyl aryl ethers lead also to functionalized organolithium compounds by reductive carbon-oxygen bond cleavage in arene-catalyzed lithiation process. Thus, the treatment of 2,3-dihydrobenzofuran (47) with an excess of lithium in the presence of a catalytic amount of DTBB in THF at 0°C gives the dianion (48) which after reaction with different carbonyl compounds and final hydrolysis with water leads to... 

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