Halides, aryl, arylation with enolate anions

Under ordinary conditions, aryl or alkenyl halides do not react with enolate anions, although reaction can occur with aryl halides bearing strongly electronegative substituents in the ortho and para positions. 2,4-Dinitrochlorobenzene, for example, with ethyl cyanoacetate gives ethyl (2,4-dinitrophenyl)cyanoacetate (90%) by an addition-elimination pathway. Unactivated aryl halides may react with enolates under more vigorous conditions, particularly sodium amide in liquid ammonia. Under these conditions, the reaction of bromobenzene with diethyl-malonate, for example, takes place by an elimination-addition sequence in which benzyne is an intermediate (1.8). 

A typical reaction is the photostimulated substitution of aryl halides by ketone [121-131] (and much less efficiently aldehyde [124]) enolate anions (Scheme 5), both inter- [121-128] and intramolecularly [129-131]. The SRN1 reaction with o-bromoacetophenones is a useful method for the construction of an aromatic ring (Scheme 24) [132-133], with o-halophenylalkyl ketones for macrocycles (Scheme 25) [134], with o-haloanilines for indoles [123], with o-halobenzylamines for isoquinolines [135], and several other heterocyclic syntheses are possible [136]. 

A particularly interesting combination of allyl ligand structure and the high reactivity toward aryl halides leads to the synthesis equivalent of nucleophilic aromatic substitution by enolate anions, but under completely different conditions (Scheme 51). In this example, the 2-methoxyallyl ligand is equivalent to an acetone enolate anion, but reacts with very different functional group compatibility (no polar... 

Another reaction that cannot be an SN2, because of the impossibility of carrying it out on an aryl halide, is the displacement from the aryl bromide 7.187. The mechanism is an Sr jI reaction (see p. 147), involving an electron transfer from the enolate 7.186 to the halide 7.187. The radical anion 7.189 loses the bromide ion to give the aryl radical 7.190, and this couples with the radical 7.188 derived from the nucleophile to give the ketone 7.191.252 The m-mcthyl group shows that the reaction did not take place by way of a benzyne. 

A nickel-catalyzed ene cyclization (sec. 11.13) has been reported that uses Ni(cod)2- The reaction proceeds by initial formation of a ac-allylnickel complex, which facilitates the intramolecular ene reaction with an allylic amine unit. l jt-Allylnickel complexes can be used in coupling reactions with both aryl and alkyl halides. Enolate anions react with nickel(O) reagents to form a complex that subsequently couples to aryl iodides. Semmelhack s final step in the synthesis of cephalotaxinone (446) treated 445 with Ni(cod)2 to... 

The photo- RNl reaction of enolate anions with aryl halides has been shown to be useful for both inter- and intra-molecular annelation reactions, but has now been found to suffer one major drawback in its general applicability. When a hydrogen atom is present at the /8-carbon of the enolate anion, hydrogen atom transfer to the transient phenyl radical is the preferred reaction pathway. 

The factors affecting the relative reactivity of aryl halides in SrnI reactions have been analysed and compared645. Competition experiments of pairs of substrates, in photo-stimulated reactions with pinacolone enolate ion in liquid ammonia, reveal a spread of reactivity exceeding three powers of ten. The ease of formation of the radical anion of the substrate appears to dominate the overall reactivity. The rate of dehalogenation of the radical anion may become important when its stability exceeds a certain threshold. When the fragmentation rate of the radical anion intermediate is fairly slow, the overall reactivity diminishes. 

Examples are the reaction of the nitronate anion 4.14 with p-nitrobcnzyl chloride 4.15, and the reaction of the pinacolone enolate 4.16 with bromo-benzene 4.17. The former might have been a straightforward SN2 reaction, but actually takes the SrnI pathway because the nitro groups make the electron transfer exceptionally easy. The latter cannot take place by a conventional Sk2 reaction, because aryl (and vinyl) halides are not susceptible to direct displacement, and the SrnI pathway overcomes this difficulty. 

One way of carrying out nucleophilic aromatic substitution reactions under mild conditions is the Ar RNl process, which is initiated by (usually, but not necessarily, photoinduced) electron transfer to an aryl halide, e.g., from an enolate Cleavage of the resulting aryl radical anion with loss of a halide anion gives an aryl radical that combines with the enolate, thus forming the desired aryl-carbon bond. 

Deprotonation. After iV,iV-diethyl-l-lithiovinylcarbamate, which is obtained by a deprotonation process (with r-BuLi as base), is converted into the organozinc reagent, it can be used to couple with aryl halides (e.g., bromides) and triflates in the presence of (dppf)PdClj to afford the enol carbamates of the acetophenones. The overall transformation can be considered an anionic equivalent of Friedel-Crafts acylation. ... 

The four most common methods for the synthesis of late transition metal enolates are oxidative addition to halocarbonyl compoxmds, ligand metathesis with main group enolates or silyl enol ethers, nucleophilic addition of anionic metal complexes to halocarbonyl electrophiles, and insertion of an a,3-imsaturated carbonyl compoimd into a metal hydride. Examples of these synthetic routes are shown in Equation 3.47-Equation 3.50. Equation 3.47 shows the synthesis of a palladium enolate complex by oxidative addition of ClCHjC(0)CHj to Pd(PPh3), Equation 3.48 shows the synthesis of a palladium enolate complex by the addition of a potassium enolate to an aryl Pd(II) halide complex, and Equation 3.49 shows the synthesis of the C-bound W(II) enolate complex in Figure 3.7 by the addition of Na[( n -C5R5)(CO)jW] to the a-halocarbonyl compound. Finally, Equation 3.50 shows the synthesis of a rhodium enolate complex by insertion of but-l-en-3-one into a rhodium hydride. This last route has also been used to prepare enolates as intermediates in reductive aldol processes. - ... 

Photoinitiation is not the only access to this chemistry, e.g., cathodic induced reduction or the use of alkali metals or other inorganic reducing reagents are also possible, but irradiation often is advantageous for preparative purposes. Since this is a chain process, the use of low-power lamps or a low quantum yield initiation step are not necessarily a limitation. Due to the requirement of a fast cleavage at the radical anion stage, aryl halides are by far the most used reagents, in particular iodides and, to a lower extent, bromides. Nucleophiles are carbanions from sufficiently acidic hydrocarbons, e.g., 1, 3-diphenylindane, fluorene or triphenylmethane [35-37] or, more commonly enolates from ketones [38], esters [39], MA -dialkylamides [40], nitriles [41]. C-C bond formation is obtained also with phenoxide or naphthoxide anions [42,43]. A few representative examples of synthetic applications of the S l... 

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