Benzylic functionalization

By careful hydrogenolysis of 19, the ebz function can be removed selectively in the presence of another benzyl function under the same conditions both functions are removed with longer reaction times lOI). Surprisingly, the same sequence with the more liable p-nitrobenzyl carbamate 21 was less selective. 

The benzyl—nitrogen bond is not so easily cleaved as the benzyl—oxygen bond, unless the O-benzyl group is sterically hindered. This difference in activity allows the selective removal of the O-benzyl function in a molecule containing both N-benzyl and O-benzyl protecting groups. The selectivity can be reversed if the amine is protected by the Cbz group. If a small amount of amine (e g., butylamine) is added, then the selective removal of N-benzyl amines can be achieved.292... 

Resistance of the deprotonated amide to attack by aUcyllithium means that two equivalents of BuLi, even at 0°C, will give the dilithiated 488 in good yield, and various electrophiles can be used to introduce benzylic functionality (Scheme 192) . 

Reaction of the dilithiated species 416 and 419 with alkyl halides, aliphatic and aromatic aldehydes, and TMSC1 leads to products 421 and 422 in modest yields (Scheme 129) [83TL4735 86JCR(S)20]. In cases of the N-benzyl amides corresponding to 415 and 418, small amounts of benzylic functionalization is observed (see also later). The methyl and carbinol derivatives corresponding to 421 and 422 were quantitively hydrolyzed into useful synthons 423 and 424, and 425 and 426, respectively. 

The benzyl p-dimethylaminobenzyl alcohol (25) is fragmented similarly with formation of p-(iV,JV-dimethylamino)benzaldehyde and toluence. Once again, the benzyl alcohol function is oxidized, the second benzyl function is reduced, and the acceptor remains unchanged it is involved only as a sensitizer. 

The first enantioselective functionalization of tricarbonylchromium arene complexes using chiral bases, to generate planar chiral chromium complexes, was reported by Simpkins and coworkers in 1994 and involved a directed orf/zo-lithiation and subsequent quench with an electrophile78. Both aromatic and benzylic functionalization of tricarbonylchromium arene complexes has been achieved. 

Other routes to this compound are possible. The illustrated route was chosen because it introduced the potential benzylic functional group and the potential carboxylic acid in one step. Notice that the aldehyde functional group and the cyclohexyl group both serve to direct the aromatic chlorination to the correct position. Also, reaction of the hydroxy acid with SOCI2 converts -OH to -Cl and -CO2H to -COC1. Treatment with H30+ regenerates the carboxylic acid. 

Benzylic functionalization. The reaction ol (toIuene)Cr(CO), (1) with KOC(CH,), and ethyl oxalate in DMSO results in the stable enol 2 in 78% yield. Similar products are formed from the reactions of (m-xylene)Cr(C()), and of (indane)Cr(CO),.-... 

Asymmetric benzylic functionalization using a chiral base can be achieved. For example, reaction of complex (58) with the chiral base (59) and methyl iodide produce complex (60) in high yield and enantiomeric excess (Scheme 100). Asymmetric benzylic alkylation can also be obtained using the chiral complex (62) derived from enantioselective deprotonation of (61) (Scheme 101). High enantiomeric excess is observed upon deprotonation and alkylation of isobenzothiophen complexes with a chiral base (Scheme 102). 

Some unusual benzylic functional groups can be reduced to hydrocarbons using NaBH4 alone in alcohols (equation 54). Choice of solvent can be used to enhance (or reduce) the reductive power of NaBIL. Thus in DMSO (or sulfolane), NaBH4 effectively reduces primary, secondary and tertiary benzylic halides to alkanes, leaving nitro, ester and carboxylic acids untouched (equation 55). There... 

As a general rule, ylides with allylic or benzylic functionality do not proceed with a high degree of stereoselectivity. There have been recent examples of arachidonic acid derivatives in which the coupling of an allylic phosphonium salt with an unsaturated aldehyde resulted in (Z)-selective alkenation. As in the case of nonstabilized ylides, replacing aromatic phosphorus substituents with allylic (113 equation 25) or alkyl (115 equation 26) groups dramaticaUy increases the production of the (, -al-kene. ... 

A number of variations of a tricyclic indole structure were prepared. Compound (8) was comparable in activity to imipramine in reversing ptosis and anticholinergic activity. Compound (9), which has the terminal N-benzyl function, was active in reversing reserpine ptosis and showed no anticholinergic and antihistaminic activity. Compound (10) was significant in that it demonstrated the importance of the location of the side chain, this form being inactive. 11... 

An intramolecular allyl silane/N-sulfonyl iminium ion cyclization has also been used as a pivotal step in an approach to the tricyclic core of the unique marine alkaloid sarain A [46]. The starting material was aziridine ester 129 (Scheme 25) which was elaborated to amide 130. An important step in the synthetic strategy was thermolysis of 130 to an azomethine ylide, which underwent stereospecific intramolecular 1,3-dipolar cycloaddition with the Z-alkene to produce bicyclic lactam 131 [47]. This compound was then elaborated into allyl silane 132. It was then possible to replace the lactam N-benzyl functionality with a tosyl moiety, leading to 133, and subsequent reduction of the carbonyl group afforded the desired cyclization precursor a-hydroxy sulfonamide 134. Exposure of 134 to ferric chloride promoted cyclization to a single stereoisomeric tricyclic amino alkene 136 having the requisite sarain A nucleus. It is believed that the intermediate N-sulfonyl iminium ion cyclizes via the conformation shown in 135. 

Because the grafting techniques described in Section 3.5.1.2 lead to rather low loading, it is of interest to incorporate functional groups directly and in large amounts into a material via a sol-gel process. Open and patent literature report colloidal silicas [23], aerogels [24] and xerogels [14] with 3-mercaptopropyl, 2-phenylethyl, or benzyl functional groups. These materials are valuable precursors to sulfonated polysiloxanes (Section 3.3). 

As it became clear that benzylic functionality was not tolerated in this system, simple methyl substituents were used, anticipating that free... 

Further studies on the dehydration of (2-hydroxyalkyl)phosphonic esters leading to alkenes , and on the dehydration of the (l-substituted-2-hydroxyalkyl)phosphonic esters (655), both conveniently with dicyclohexylcar-bodiimide, have further confirmed the direct correlation between ZIE composition of the resultant alkene and the erythrolthreo composition of the substrates. A similar treatment of the sterically hindered j5-hydroxyalkyl ester (656), has provided isolable examples of the 1,2-oxaphosphetanes (657) (R = CHjPh or other benzylic function). At 50 °C 657 (R = CH2Ph) decomposes to the expected alkene, H2C=C(CH2ph)2 as the major product (60%), together with the expected dehydration products of the alcohol 656 (ca 30%), ethyl methyl (2,4,6-triisopropylphenyl)phosphonate, and smaller amounts of other esters. Such results do not, of course, demonstrate the formation of 1,2-oxaphosphetanes in the WEH reaction. 

Additional studies of the acid-catalysed rearrangement of 1,2-dihydroiso-quinolines have been carried out, and it has been shown that a C-1 allyl group migrates more readily than a benzylic function. ... 

Selective ortho and benzylic functionalization of secondary and tertiary p-tolylsulfonamides is investigated (eq 47). For both R = H and R = Et, kinetic ortho metalation is achieved using BuLi, while thermodynamic conditions lead to ortho and benzylic deprotonation, respectively. Regioselective metalation of secondary sulfonamides, R = H, is achieved by using BuLi/KOtBu superbase. ... 

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