Electrophiles benzylic

Conjugation in allylic or benzylic electrophiles can also stabilize the corresponding carbocations and thereby facilitate substitution by the SnI mechanism, as shown by the relative solvolysis rates given in Table 4.2. 

Donor-substituted benzylic electrophiles usually undergo clean Sn2 or SnI reactions to yield the expected products in high yield. The favorable electronic effect of the aryl group seems to dominate the reaction, and sterically demanding substitu-... 

Benzylic electrophiles bearing electron-withdrawing groups at the arene do not always yield the expected products of nucleophilic substitution on treatment with a nucleophile. One important side reaction is the dimerization of these compounds to yield 1,2-diarylethenes (stilbenes). This dimerization does not require such highly activated systems as the example sketched in Scheme 4.28, but can even occur with, for example, 2- or 4-nitrobenzyl chloride [120, 121]. The latter compounds are converted into the corresponding stilbenes by treatment with KOH in ethanol [120]. Di-arylmethyl halides behave similarly and can yield tetraarylethenes on treatment with a base. These reactions presumably proceed via the mechanism sketched in Scheme 4.27, in which the amphiphilic character of the nitro group plays a decisive role (metalated nitroalkanes or 4-nitrobenzyl derivatives can act as nucleophiles and as electrophiles). 

Other benzylic electrophiles which can lead to unexpected products are 1,2- or l,4-bis(halomethyl)benzenes. On treatment with a nucleophile, oxidation of the nucleophile instead of nucleophilic substitution may occur, followed by the formation of highly reactive quinodimethanes, which can either oligomerize or undergo addition or cycloaddition reactions (Scheme 4.29). The outcome of these reactions can, however, be controlled by choosing the right conditions, as demonstrated by the numerous report of successful Sn2 reactions at 1,2- or l,4-bis(halomethyl)benzenes (see, e.g., Ref. [125]). 

Nitrile-stabilized anions are so nucleophilic that they will react with alkyl halides rather well even when a crowded quaternary centre (a carbon bearing no H atoms) is being formed. In this example the strong base, sodium hydride, was used to deprotonate the branched nitrile completely and benzyl chloride was the electrophile. The greater reactivity of benzylic electrophiles compensates for the poorer leaving group. In DMF, the anion is particularly reactive because it is not solvated (DMF solvates only the Na+ cation). 

The second amine can be made by reductive amination of a ketone so we need to think how - -ketone might he made by enolate alkylation. It is ideal for alkylation of an enol or enolate wit . benzyl electrophile. You could have chosen a number of specific enol equivalents for this, we use r -c.iaiLiuic. 

See p. 431 of the textbook for a reminder about the reactivity of benzylic electrophiles. 

Benzylic Electrophiles. Benzylic chlorides and bromides are widely and readily available. They are therefore the reagents of choice in most cases. Less readily available benzylic iodides and fluorides have hardly been used. More recently, the use of benzylsulfonium salts in Pd- or Ni-catalyzed cross-couphng has been reported. 

Scheidt recently reported that a-silyl alkoxides generated from a-silyl silylethers 79 by fluoride-induced desilylation instead of deprotonation of a-silyl alcohol can be trapped by primary alkyl and by allylic and benzylic electrophiles via a Brook rearrangement (Scheme... 

These reactions are likely to occur by oxidative addition through a radical mechanism, as evidenced by the loss of stereochemistry of the starting alkyl halide during the coupling process (Equation 19.14b). Despite the radical mechanism, some reactions of benzylic electrophiles have been conducted enantioselectively (Equation 19.14c). Even reactions of alkylboron reagents witti secondary alkyl halides catalyzed by nickel complexes have now been reported. These reactions were conducted with nickel precursors in combination with trflns-l,2-cyclohexanediamine (Equation 19.14d). ... 

Selected apphcations are shown in Scheme 60. The reaction is highly stereoselective, imines from a-ketoaldehydes yielding mostly or exclusively c -azetidinones, whereas imines from benzaldehydes yield only tron -isomers. The approach has been extended to benzyl electrophiles in place of allyl phosphates. A synthesis of cephems using this novel [2 + 2] cycloaddition has been reported by Zhou and Alper. This method represents a potential entry into the medicinally important class of /3-lactam antibiotics, and further applications are expected. 

Pd-catalyzed benzylation shares some fundamental features with Pd-catalyzed allylation. However, it is less complicated and generally more favorable than allylation, even though oxidative addition of benzylic electrophiles with Pd is kinetically less favorable than that of allylic electrophiles. Much of these differences between benzyl and allyl may be attributable to the fact that the li,y rr-bond in benzyl is part of an aromatic ring system and is hence less reactive toward Pd than that in allyl. Some fundamental features of the benzylic reagents in Pd-catalyzed cross-coupling are summarized in Table 6. 

Benzylic Electrophiles. BenzyUc chlorides and bromides are widely and readily available. They are therefore the reagents of choice in most cases. Less readily available benzylic iodides and fluorides have hardly been used. More recently, the use of benzylsulfonium salts in Pd- or Ni-catalyzed cross-coupling has been reported. These results are interesting in view of the fact that metal-mediated cleavage of the C—S bond has been shown to be an important biological process. It is not clear, however, in what cases this reaction would turn out to be the synthetic method of choice in preference to the corresponding reactions of benzyl chlorides and bromides. 

Reaction with Allylic and Benzylic Electrophiles. The acyl radicals can be trapped with halogen- and silicon-based electrophiles. a -Allylation of a, -unsaturated ketones is done while using Mn(OAc)3 dihydrate and allyl bromide in refluxing benzene (eq 29). Better yields are usually observed for cyclopen-tenones compared to cyclohexenones. a -Benzylation is also possible using benzyl bromide as the electrophilic partner (eq 30). Both methods tolerate a range of substitution, including 8-alkoxy-a, -unsaturated ketones. It is possible to perform a sequential allylation/cyclization with an excess of allyltrimethylsilane (eq 31). Mn(OAc)3 offers good conversions, but the use of ceric ammonium nitrate (CAN) as co-oxidant improves yields. 

Potassium acetate is used as the source of acetate anion in a range of addition and substitution reactions of activated cyclopropanes, epoxides, alkyl, aUyl, and benzyl electrophiles. 

Model 12 What about allylic and benzylic electrophilic carbons ... 

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