Regioselectivity toluene benzylation

That the reductive cleavage is compatible with the presence of 0-acyl groups raises the question of whether the regioselectivity may be changed back to that of LiptSk-Ntoisi. Indeed, when the solvent is changed from tetrahydrofuran to toluene and the reduction system to MejNBHj-AlClj, a free 6-OH and O-benzyl at C-6 is produced (Scheme 9) [27]. 

Partial benzylation with powdered potassium hydroxide as a base and toluene as a solvent was used some 50 years ago for the preparation of 1,6-anhydro-2,4-0-benzyl-P-D-glucopyranose [79]. Since that time, other solvents, such as benzene [80-82], 1,4-dioxane-toluene mixtures [83, 84], or excess benzyl chloride [82, 85] were used as well, with apparent effects on the regioselectivity. Thus, the axially oriented secondary hydroxyl group of lL-l,2,3,4-tetra-0-benzyl-c/i ro-inositol is more reactive than the equatorial one using benzyl chloride alone (ratio of 79 21), whereas the opposite is true (35 65) in benzene as a solvent [82]. Benzylation of myo-inositol derivatives in the latter solvent was also described [80, 81, 86]. 

According to the principle of least nuclear motion [45] aromatic deprotonation should be faster than benzylic metalation, because the benzylic carbanion is expected to rehybridize slightly toward sp2 to achieve stabilization by conjugation with the aromatic n system. This is, in fact, often observed [217, 401, 423-425], but with some substrates benzylic metalation can effectively compete with aromatic metalation[181, 425, 426] (Scheme 5.47). Thus, treatment of toluene with BuLi/TMEDA or BuLi/DABCO at 80 °C for 0.5 h or with BuLi/KOtBu in Et20 at -20 °C for 4 h leads to clean formation of benzyllithium [85, 427, 428], The kinetic preference for aromatic deprotonation, because of the principle of least nuclear motion, thus seems to be too weak to control the regioselectivity of deprotonations in all instances. 

Irradiating at rather short wavelengths (approx. 300 nm) is essential for realizing the unique regioselectivity. When short wavelengths (below 325 nm) were cut off, the weakest C-H bonds were carbonylated methylene in alkanes and benzylic methyl in toluene (Scheme 7). 

The regioselectivity of the benzylation of toluene shifts from ksubpara > ksub ortho >... 

A further useful application of SC-CO2 as a reaction medium is the free-radical side-chain bromination of alkylaromatics, replacing conventional solvents such as tetra-chloromethane or chlorofluorohydrocarbons having no abstractable hydrogen atoms [920]. For example, bromination of ethylbenzene in SC-CO2 at 40 °C and 22.9 MPa yields 95 cmol/mol (1-bromoethyl)benzene, with practically the same regioselectivity as obtained in conventional tetrachloromethane as the solvent. Even the classical Wohl-Ziegler bromination of benzylic or allylic substrates using A-bromosuccinimide (NBS) can be conducted in SC-CO2 [920]. Irradiation of a solution of toluene, NBS, and AIBN (as initiator) in SC-CO2 at 40 °C and 17.0 MPa for 4 hours gave (bromomethyl)-... 

The reaction of 1,2 4,5-diketals 49 with a variety of electrophiles has been reported, and it was found that the use of a limited quantity of the reagents and control of reaction temperature may result in a fairly good regioselective monosubstitution at the 3 position. Benzylation of dicyclohexylidene-myo-inositol 49a with benzyl bromide in the presence of NaH under toluene under refluxing conditions was reported to produce selectively the 3-benzyl ether 51 (R=Bn) in 70 (Ref.13a) and 60%27 yields (Scheme 3-2). Benzylation21 28 and allylation-221 using BaO and Ba(OH)2 in DMF afforded successfully the 3-alkylation products 51 (R=Bn and All) in 70 and 68% yields respectively. These authors claimed that combination-27 of BnBr and NaH resulted in poorer selectivity (48%... 

The regioselectivity of the reaction with methyl benzyl ketone depends on the conditions under which it is conducted and on the substituent R at the nitrogen atom of the isatoic anhydride. Thus, after treatment of this ketone with lithium diisopropylamide (-78°C, 1 h), addition of the unsubstituted anhydride 1, and treatment of the reaction mass between -78°C and 20°C a mixture of compounds 39 (R = H) (yield 30%) and 40 (yield 34%) was obtained. Under analogous conditions, but with briefer treatment of the ketone with lithium diisopropylamide (0.5 h), in both cases only the isomers 39 (with R = Me yield 80%, with R = z-Pr yield 82%) were obtained from the anhydrides 2 (R = Me) or (19) (R = z-Pr). One isomer 39 (R = Me) was also obtained with a yield of 56% when the ketone was treated with potassium bis(trimethylsilyl)amide in toluene and THF in a nitrogen atmosphere (-78°C, 1 h), the anhydride (2) in THF was added, and the mixture was kept at -78°C for 5 min [23]. 

Addition of caesium fluoride to the reaction gave a 2 1 ratio of 3- to 2-0-benzyl ethers. The regioselective benzylation of some methyl hexopyranosides has been studied (i,Bu2SnO, toluene ii,BnBr, 85°C). Generally the same products were obtained as with (Bu3Sn)20, but often in better yields. ... 

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