Arylation of anilides

Several reports have appeared describing anilide arylation by arenes that do not involve coupling of a C-H bond with a C-Hal bond and thus will be discussed only briefly. Buchwald has shown that oxidative arylation of anilides takes place in presence of 5-10 mol% of palladium acetate and catalytic DMSO in trifluoroacetic acid solvent by using oxygen as the terminal oxidant [52], Pivalanilides afford the best results. Notably, only about four equivalents of the arene component are required for efficient arylation. However, regioisomer mixtures were obtained if monosubstituted arenes were used as the coupling components. 

An elegant application of regioselective palladium-catalyzed direct arylations of anilides in the presence of stoichiometric amounts of AgOAc in trifluoroacetic acid [65] permitted the preparation of chiral diamines with varying steric demands (Scheme 9.28) [66]. 

The Marsden group has published a collection of articles detailing the synthesis of heteroatom containing C3 quatemized oxindoles [64—66]. The transformations involved the palladium-catalyzed intramolecular arylation of anilides bearing either amino or alkoxy functionality alpha to the anilide carbonyl. Under microwave conditions, a variety of 3-alkoxy-3-aryl, 3-amino-3-aiyl, or 3-amino-3-alkyloxin-doles have been prepared in racemic form. In one example, 3-indolyloxindole 1 7 was prepared in 65% yield (Scheme 28). 

The directed C—H bond activation of arenes is an established technique for the regioselective functionaHzahon of (het)arenes (see Chapters 9 and 10), and was also appUed to the regioselective oxidative Mizoroki-Heck arylation of anilides (181 183 Scheme 7.44) [117]. 

Three reviews have detailed progress in the formation of biaryl systems using metal-catalysed substitutions of carbon—hydrogen bonds. The preferential arylation at the para-position of phenol and aniline derivatives with diaryl iodonium salts has been achieved using copper catalysis. Under similar reaction conditions, a-arylacetamides are selectively arylated at the meta-position. A mechanistic study, including DFT calculations, suggests that the meta-selectivity in the copper-catalysed arylation of anilides derives from a Heck-like four-membered transition state involving a Cu(III)-phenyl species (47). 

With Copper In 2009, Gaunt s group [30] reported a wieta-selective Cu-catalyzed direct arylation of anilides with diaryliodonium salts, which was expected from a S Ar mechanism (Scheme 4.6). This was achievable by the coordination of the amide carbonyl group with the metal that managed to override the natural selectivity of these S Ar reactions. [31] This proposal was backed up by computational studies. In Scheme 4.6, we compare the selectivity of the Cu-catalyzed pathway with the Pd-catalyzed pathway. 

Brasche G, Garcia-Fortanet J, Buchwald SL (2008) Twofold C-H fimctionalizaticm palladium-catalyzed ortho arylation of anilides. Org Lett 10 2207-2210... 

These ideas will be discussed in the following subsections, where most of the attention will be devoted to the mechanistic smdies with aromatic esters, which have been the subject of an overwhelming majority of the research efforts. Nevertheless, the same reaction mechanism has been shown to be valid for the PFR of anilides, thioesters, sulfonates, and so forth. Furthermore, it is also applicable to the photo-Claisen rearrangement [i.e. the migration of alkyl (or allyl, benzyl, aryl,)] groups of aromatic ethers to the ortho and para positions of the aromatic ring [21,22]. 

Table 3.26 lists illustrative examples of cleavage reactions of support-bound N-aryl-carbamates, anilides, and /V-arylsulfonamidcs. /V-Arylcarbamatcs are more susceptible to attack by nucleophiles than /V-alkylcarbamates, and, if strong bases or nucleophiles are to be used in a reaction sequence, it might be a better choice to link the aniline to the support as an /V-bcnzyl derivative. Entry 7 (Table 3.26) is an example of a safety-catch linker for anilines, in which activation is achieved by enzymatic hydrolysis of a phenylacetamide to liberate a primary amine, which then cleaves the anilide. 

The recent literature presented some improvements of the known procedures rather than new synthetic approaches. An efficient and more sustainable protocol for the copper-catalysed intramolecular O-arylation of ortho-halo anilides to afford benzo[<7]oxazoles has been described. After an optimization process, the best conditions were the use of CuCl and TMEDA in water... 

We reasoned that the arylation of benzamide derivatives should also be possible under Pd(II)-Pd(IV) couple conditions. Gratifyingly, conditions that were developed for anilide arylation worked well for benzamide arylation (Scheme 12) [57],... 

A series of aryl radical cyclizations were reported by a group at Novartis [10], and some of these processes were also compared with bond formation by Pd-mediated Heck cyclization of the same substrates. The tributyltin hydride-mediated reaction of iodo alkenes 7 (Scheme 3), immobilized on polystyrene resin through a linker, gave dihydrobenzofurans 8 [11]. It was also possible to perform a tandem cyclization using allyltributyltin to give the allylated product 9, although the yields were less satisfactory. The radical cyclization onto enol ethers was demonstrated [12] by the conversion of 10 to 11. For best results, the tributyltin hydride and AIBN were added portionwise every 5-8 h. The impressive 95% yield was in fact higher than that for the solid-phase Heck cyclization of 10. Similarly, cyclization of anilide 12 afforded the phenanthridine 13. 

Various heterocycles 860 can be synthesized by the treatment of unsaturated aryl amides, carbamates, thiocarbamates and ureas 859 with IBX (Scheme 3.343) [1176,1177]. The mechanism of this reaction has been investigated in detail [1178]. On the basis of solvent effects and D-labeling studies, it was proposed that the IBX-mediated cyclization of anilides in THF involves an initial single-electron transfer (SET) to a THF-IBX complex followed by deprotonation, radical cyclization and concluding termination by hydrogen abstraction from THF [1178]. A similar IBX-mediated cyclization has been applied in the synthetic protocol for the stereoselective preparation of amino sugars [1179]. 

Miura reported the directing-group-assisted C-H arylation of aromatic ketone 9 [9a,b], anilide 11 [9c], and aldehydes [9d] (Scheme 17.3). 

Following the report described in Scheme 24.23, Buchwald group published an example for the aerobic CDC of anilides with arenes (Scheme 24.24) [25]. The use of TFA is critical for the efficiency of these arylations. Unlike the reactions in Scheme 24.23, the CDC of anilides 24 with monosubstituted arenes leads to small amounts of the ortho-hiaryl product along with the meta- and / ara-isomers. 

Gaunt and coworkers discovered that anilides were selectively wcta-arylated in the presence of Cu(OTf)2 in DCE at 70 °C (Scheme 16b) [80]. In a similar fashion, the group achieved the para-arylation of anilines and phenol ethers, and the meta-arylation of a-arylacetamides and a-arylketones [217, 218]. Unsymmetric salts with mesityl or TRIP dummy substituents could be chemoselectively employed, and the reactions also proceeded in the absence of copper at slightly higher temperature, which makes mechanistic interpretations difficult [43]. 

The arylation of sodium cyanide can be achieved in moderate yields with electron-withdrawing iodonium salts [87]. The synthesis of esters was achieved by palladium-catalyzed carbonylative reaction of alcohols with diaiyliodonium salts under a CO atmosphere [262]. More recently, a base-mediated arylation of qui-nones with electron-donating iodonium salts in refluxing DCE was reported in moderate to good yields [263]. Quinoline anilides could be arylated at the P-carbon by a Pd- or Ni-catalyzed reaction proceeding via activation of sp C-H bonds (Scheme 22a) [264, 265]. Vinyl isocyanides were arylated at room temperature in a photoredox-catalyzed system with an iridium catalyst and visible light, followed by cyclizatimi to give isoquinoline derivatives [266]. 

Silver acetate promoted iodine removal and palladium-catalyzed coupling of aryl iodides and (V-acylated anilides produced ortho-aryl acylated anilides, which were then hydrolyzed to give 2-aryl or 2,6-diarylanilines. This silver-ion assisted palladium-catalyzed aryl-aryl coupling was general (53-96% yields) and showed functional group tolerance for chloride and bromide substituents in either the aryl iodides or anilides (eq 16).i ... 

The room teiiq erature reaction of simple aliphatic ketones with an aqueous solution of thalllum(III) chloride leads to the formation of the mono-oxoalkylthalllum(III>. derivatives (23) which are then converted to selectively monochlorinated a-monochlorlnated ketones (Scheme 9> . Methyl vinyl ketone Is 8 arylated by arylthalllum conq>ounds In a reaction which Is catalysed by lithium tetrachloropalladate (Scheme 10) . The thallatlon of anilides with thalllum(III) trifluoroacetate In a mixture of trlfluoroacetlc acid and ether affords the ortho-thallated derivatives (24>, which yield 2-acetamldotolanes on reaction with copper(I> phenylacetyllde In acetonitrile. Ortho-... 

The effect of the substituents on the reaction rates were studied on a series of /7-aryl-substituted anilides 7. Electron-donating substituents (R = MeO) resulted in an increase in the reaction rate, whereas electron-withdrawing substituents caused a decrease in the reaction rate (R = Cl, COMe) or had no significant effect on the rate (R = F). For anilides with R = NO2 or CF3 no reaction occurred. The Flammett plot gave a linear graph with a negative slope and the better correlations were found with parameters (Fig. 39.1). 

The kinetic experiments were run to decide whether the rate-determining step of the reaetion was the SET (formation of radical cation I) or the radical cycliza-tion step (transformation of II into III). The first set of data was obtained from aryl-substituted anilides 7 (Fig. 39.1), in order to get information about the influence of the electronic effects on the reaction rate and hence about the possible formation of a radical cation in the slow step. 

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