Arylation of Amides

These authors decided to investigate the intramolecular variant of this reaction that would generate oxindoles. Unfortunately, the protocol described previously for the a-arylation of DMA was less 

Asymmetric organocatalytic a-arylation of aldehydes, as described by Jorgensen and cowork- 

In 2001, Lee and Hartwig [77] screened many more ligands in this arylation reaction. They reported that the more hindered alkylphosphanes were not effective for these reactions, but that slightly less sterically demanding PCyj provides fast reaction rates and full conversion for the synthesis of oxindoles by a-arylation of ortfro-bromoanilines or the corresponding ortho-chloro derivatives at 50-70 °C in the presence of NaOfBu. In addition, they found that NHC ligands 

In 2008, Marsden and coworkers [86] extended the paUadium-cattilyzed intramolecular arylation of o-haloanilides to the synthesis of valuable quaternary 3-aminooxindole molecules. Specifically, these compounds were prepared by the rapid microwave-promoted intramolecular arylation of A7-(2-bromophenyl)-A/ -methyl-2-dialylaminoacylamines, in the presence of NaOtBu as the base and a 

The intermolecular a-arylation of amides with aryl chlorides was unknown until very recently. Fortunately, the work developed by Walsh and coworkers [93] has demystified the theme. Aryl chlorides are generally less reactive than aryl bromides in oxidative additions nonetheless, aryl chlorides are less expensive and more readily accessible when compared with aryl bromides, making their use in cross-coupling reactions highly desirable. Walsh and coworkers reported the first deprotonative cross-coupling process for the intermolecular arylation of amides with aryl chlorides. Buchwald-type [94] precatalysts formed with Kwong s [95] indole-based phosphane ligand effectively catalyzes the 

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These conditions were also successfully applied to arylation of amides and carbamates. 

Palladium acetate in conjunction with a diphosphine ligand, xantphos, is active for arylation of amides, ureas, oxazolidinones and sulfonamides.174... 

The intermolecular coupling of lactams and acyclic amides has also been reported. Reactions of carbamates with aryl halides occurred in the presence of catalysts ligated by P(/-Bu)3.78 Both carbamates and amides coupled with aryl halides in the presence of a catalyst bearing Xantphos.90 In addition, the coupling of lactams with aryl halides has been successful. A combination of Pd(OAc)2 and DPPF first formed A-aryl lactams in good yields from 7-lactams, but the arylation of amides was improved significantly by the use of Xantphos (Equations (20) and (21)).90 91 The reaction of aryl halides with vinyligous amides has also been reported 92... 

Hartwig has reported the asymmetric intramolecular arylation of amides using a chiral carbene ligand (5) with up to 76% ee [43]. 

A procedure has been developed for the palladium-catalysed a-arylation of amides by aryl bromides using the zinc enolates of the amides. The reaction works well with bromoarenes carrying a variety of ring substituents and with bromopyridine. In addition, the reaction has been shown to be effective with morpholine amides to give products which are precursors for aldehydes and ketones.39 A new method has been reported for the allylation of aryl halides using homoallyl alcohols as the allyl source the palladium-catalysed reaction, which may be both stereo- and regio-sepecific, uses a retro-allylation reaction to form a a-allyl(aryl)palladium intermediate.40... 

N-Arylation of amides.2 Bromo- or chlorobenzenes ary late amides in the presence of TDA-1 and CuCl (1 5). 

A variety of N-H containing compounds are A-arylated by Ar3Bi in the presence of a stoichiometric amount of Cu(OAc)2, 155-161 which plays dual important roles it oxidizes Ar3Bi to Ar3Bi(OAc)2 and mediates the arylation via transmetallation (Equation (94)). In the presence of Et3N or pyridine, the Cu(OAc)2-promoted A-arylation of amides, sulfonamides, ureas, carbamates, and anilines with Ar3Bi occurs much more efficiently than the reaction without a... 

N-Arylation of amides was also performed by the author using (CuOTf)2 benzene and CS2CO3 with co-catalysts, 1,10-phenanthroline and dibenzylidene acetone, as illustrated in Eq. 1 below ... 

The coupling of amides and aryl halides or sulfonates is a highly desirable transformation since amides are ubiquitous in biologically active compounds. The arylation of amides however, is considerably different from the analogous reactions of amines since their pKas, and thus their relative reactivities, are considerably different. 

A-Alkylation or A-Arylation of Amides and Imides Acylamino-de-halogenation... 

N-Arylaminophthalimides, hydrazines, hydrazones, and N-H containing heterocycles are N-arylated by combined use of Ar3Bi and Cu(OAc)2 (Scheme 14.134) [281] in which Cu(OAc)2 oxidizes Ar.l i to Ar jl i(OAc)2 and catalyzes the arylation via transmetalation (Section 14.3.4.2). The Cu(OAc)2-promoted N-arylation of amides, sulfonamides, ureas, carbamates, and anilines with ArsBi proceeds efficiently in the presence of EtsN or pyridine (Scheme 14.135) [282]. N-Arylation occurs selectively on the primary amino group of aminobenzanilides (Scheme 14.136) [283]. A variety of amines are N-alkylated in moderate yields by use of alkylbismuthanes assisted by Cu(OAc)2 [284]. 

Under the conditions suitable for the A -arylation of amidic nitrogen atoms, (see section 7.6.1), reaction of p-ketoanilides with 4-methylphenyllead triacetate (67) in the presence of sodium hydride and copper diacetate afforded only products of C-arylation (68), although in poor yields (11-33%). The a-aryl-p-ketoanilides are unstable in solution and easily oxidised by air to the a-aryl-a-ketoanilide (69), also isolated in modest yields (8-19%). 1 3... 

With the additive 2-oxazoUdinone in DMSO to assist Cul at 120°, A-arylation of amides (lactams) is readily performed. A more commonly used ligand is 1,10-phenanthroline, as it is applied also to form iV-(aryl)alkoxyamines from RNHOR. In A-arylation of iV-heterocycles (indole, pyrrole, imidazole, pyrazole,...), l,3-di(2-pyridyl)-l,3-propane-dione appears to be a useful ligand for Cul. ... 

A study of A-arylation of amides has shown the effect of product yields on critical structural feature of the X-Phos-type (2-di-t-butylphosphinobiaryl) hgand. It appears that... 

Arylation. For A-arylation of lactams with ArBr, a catalytic system composed of Pd(OAc)2, l,l -bis(diphenylphosphino)ferrocene, and f-BuONa has been employed. For arylation of amides, and amines, " Xantphos (1) appears to be the ligand of choice. 

Inter- and intramolecular arylations of amides have been described [68]. Use of zinc enolates of amides affords high yields in some cases (Eq. 23) [69]. In the... 

The cross-coupling of aryl halides and enolates is a powerful method to generate new C-C bonds and it has been extensively investigated using various palladium catalysts [70]. Extremely active NHC/Pd systems have been reported for the a-arylation of esters at room temperature [71] and for the arylation of amides [72]. Ketones that possess a-protons can be deprotonated in the presence of strong bases, a-Arylation of ketones can be performed in the presence of a catalytic amount of (NHC)Pd(allyl)Cl as catalyst and NaO Bu as base (Scheme 19). 

The copper-promoted arylation of amides is known as the Goldberg reaction. Similar to the traditional Ullmann reaction, this transformation suffered from high reaction temperatures and strictly Umited substrates. The introduction of suitable Ugands has changed this situation. 

Recently, ethyl 2-oxocyclohexanecarboxylate (L19) [27] also showed good activity for the arylation of amides (entry 7). Interestingly, the reaction even worked at room temperature for some aryl iodides. 

Pd(0)-Catalyzed Reactions of sp Organic Halides and Pseudohalides 3.7.3.4 Arylation of Amides, Carbamates, and Azoles... 

Secondary phosphine oxides were used as ligands/preligands in palladium catalysts that were useful in the Suzuki-Miyaura coupling, in intramolecular ot-arylations of amides and in the arylation of indoles. ... 

The intramolecular version of Pd-catalyzed a-arylation of amides is considerably more favorable than its intermolecular version (Scheme 26). 

Scheme 1.7 Copper-catalyzed arylation of amide 21 (Goldberg, 1906).

As the intermolecular arylation of amides is hampered by their relatively high pKi-values, the double arylation becomes more relevant, since the pfQ of the monoarylated amide is significantly lower than that of the starting material. 

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