A-arylacetamides

N, A-Dialkylacetamide enolate ions (143) were proved to react with aryl halides in liquid ammonia giving A,A-dimethyl-a-arylacetamides together with some A,A-dimethyl-a, a-diarylacetamides189. In order to synthesize some herbicides of the amide family, a series of A,A-dimethyl a-aryl and a,a-diaryl acetamides were prepared by the reaction of aryl halides (Phi, /7-iodoanisole, / -iodotoluene, 1-iodonaphthalene, 9-bromophenan-threne, 9-bromoanthracene and/ -iodobenzoic acid) with 143 (equation 95)190. The product distribution was shown to be dependent on the 143/aryl halide ratio. With a ratio of 5, approximately 50% of 144 and 20% of 145 were obtained. 

Azidoalkyl a-diazoketones have been reacted with A-phenylmaleimide, yielding, for example, the 4,6-dioxo-3a,4,6,6a-tetrahydro-l//,5//-pyrrolo[3,4-6 ]-1,2,3-triazole (163) <84KGS514>. Similarly, 2-azido-A-arylacetamides have been reacted with /V-phenylmaleimide to yield, for example, 4,6-dioxo-3a,4,6,6a-tetrahydro-l//,5//-pyrrolo[3,4-6 ]-l,2,3-triazole (164) <92MI 703-oi>. Various co-azido-alkyltriphenylphosphonium bromides have also been reacted with TV-phenylmaleimide giving, for example, 4,6-dioxo-3a,4,6,6a-tetrahydro-l//,5//-pyrrolo[3,4-6 ]-l,2,3-triazole (165) <92BSF308>. 

During the studies shown in Scheme 20.31. the authors noticed that, in some cases, the spirocyclic system was not the reaction product Instead, they obtained a rearranged conpound 172, probably resulting from an intramolecular aryl transfer as shown in Scheme 20..3.3. This transformation, initiated by Pummerer chemistry provides a new synthesis of a-arylacetamides, which are present in a large number of active molecules. ... 

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). 

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 synthesis of N,N-disubstituted-a-arylacetamides can be achieved by reaction of haloarenes with carbanions from N,N-disubstituted amides in liquid ammonia under light initiation. The potassium salt of N-acetylpiperidine does not react, probably due to its low solubility in liquid ammonia. The anions derived from acetamide and N-methyl acetamide are also unreactive. ... 

The diazonium salts 145 are another source of arylpalladium com-plexes[114]. They are the most reactive source of arylpalladium species and the reaction can be carried out at room temperature. In addition, they can be used for alkene insertion in the absence of a phosphine ligand using Pd2(dba)3 as a catalyst. This reaction consists of the indirect substitution reaction of an aromatic nitro group with an alkene. The use of diazonium salts is more convenient and synthetically useful than the use of aryl halides, because many aryl halides are prepared from diazonium salts. Diazotization of the aniline derivative 146 in aqueous solution and subsequent insertion of acrylate catalyzed by Pd(OAc)2 by the addition of MeOH are carried out as a one-pot reaction, affording the cinnamate 147 in good yield[115]. The A-nitroso-jV-arylacetamide 148 is prepared from acetanilides and used as another precursor of arylpalladium intermediate. It is more reactive than aryl iodides and bromides and reacts with alkenes at 40 °C without addition of a phosphine ligandfl 16]. 

In all the diazotization reactions discussed in Sections 2.1-2.4 an equimolar amount of water is formed as byproduct. There are two general pathways for obtaining diazonium salts without formation of water. One is based on the rearrangement of 7V-nitroso-7V-arylacetamides, the other on the nitrosation of a monoarylated sp2-hybridized nitrogen compound by nitrosating reagents XNO in which X is a weak nucleophile. 

Iodosobenzene diacetate is used as a reagent for the preparation of glycol diacetates from olefins,9 for the oxidation of aromatic amines to corresponding azo compounds,10 for the ring acetylation of N-arylacetamides,11 for oxidation of some phenols to phenyl ethers,12 and as a coupling agent in the preparation of iodonium salts.13 Its hydrolysis to iodosobenzene constitutes the best synthesis of that compound.14... 

This subsection is devoted to the metabolic reactivity of the amide bond in anilides, i.e., compounds whose amino moiety is attached to an aromatic ring. Based on the nature of the acyl moiety, a number of classes of anilides exist, three of which are of particular interest here, namely arylacetamides, acylani-lides, and aminoacylanilides. The first group contains several analgesic-antipyretic drugs, the second A4-acyl derivatives of sulfonamides, and the third a number of local anesthetics. Particular attention will be paid to structure-metabolism relationships in the hydrolysis of these compounds. Cases where hydrolysis leads to toxification will be summarized in the last part of the chapter. 

Tertiary arylacetamides appear to undergo hydrolysis to a very limited extent only. Hydrolysis of the synthetic opioid fentanyl (4.117) to despropa-noylfentanyl (4.118) was a very minor pathway in humans [76], No metabolites resulting from amide hydrolysis were detected for the fentanil analogues alfentanil (4.119) and sufentanil (4.120) [77], for which oxidative N-dealkylation was the main metabolic pathway. 

The Sankyo company have shown that conformational restriction of the arylacetamide fragment of the Zambeletti/Glaxo series as in the indane derivative (49) preserves kappa selectivity (kappa A) = 0.67 nM, mu K, = 698 nM, mouse phenylquinone-induced writhing ED50 = 1.3 mg/kg s.c.) [72]. This aromatic group contains two of the rings found in the acenaphthene derivatives (26, 27) described above. 

Several substitution reactions are catalyzed by iron ions (Galli Bunnett 1984). A detailed preparative study was recently reported on the ferrous ion-initiated SrnI reactions of haloarenes with the sodium enolates of tcri-butyl acetate, /V-accty I morpholine and a number of higher A-acylmorpholines. Smooth and rapid substitution occurs and good to excellent yields were obtained of arylacetic esters, arylacetamides, and arylalkyl amides. The... 

Another U50488-derived irreversible k receptor antagonist, DIPPA (95) was described by Portoghese and his collaborators [149, 150]. The design of DIPPA (which has also an isothiocyanate acylating group) as an affinity label was based on the report that arylacetamide (96) was a potent, k selective... 

Adducts from POCI3 and formamides, acetamides, - malono ester amides, - cyanoacet-amides - or lactams have been transformed to amidines by reaction with the following amino compounds 2-acylaminothiophenes, 2-aminoisoxazole, 4-aminotriazole, 3-aminoimidazole, ° aminoindoles, " 2-acylaminoanthraquinones, 2,6-diaminoanthraquinone, 6-aminouracil, -arylacetamides, A -disubstituted thioureas IV-arylchloroacetamides, anilines, o-phe-nylenediamines, anthranilic acid amide and acylaminobenzothiophene. ... 

It has been proposed to use hemoglobin adducts in biomonitoring, as a dosimeter for the biologically active dose of arylamines/arylacetamides. This may also provide information about the individual susceptibility to the toxic and carcinogenic effects of these chemicals30,31. Field workers exposed to Propanil (38), a major herbicide in rice paddies,... 

In our previous study using the SUPERPOSE program, which does not require an anchor point, the arylacetamide U-50488H was superposed on the morphinan TRK-820 [16]. This model indicated a basic amine and an amide side chain as overlapping points (Fig. 12). 

Fig. 12 Our previous superimposition of U-50488H (arylacetamide) on TRK-820 (morphinan) [16]. TRK-820 is shown in green, and U-50488H is shown in white. Sphere colors indicate the following properties (see Sect. 4.3) hydrophobic (HP, white) aromatic (AR, green) hydrogen-bond donors (HD, blue) hydrogen-bond acceptors (HA, red) and hydrogen-bond donors/acceptor (DA, violet). Large and small spheres represent radii of 1 and 0.5 A, respectively. The TRK-820 and U-50488H spheres are represented by dotted and solid spheres, respectively. Only matched spheres are indicated...

Fig. 13 Docking models of an arylacetamide, the derivative of DuP 747 yellow), and a benzomorphan, MPCB (cyan), reported by Lavecchia et al. [36]. Reprinted from [36] with permission from American Chemical Society. Copyright (2000)...

Structural characterization of a-phenylsulfonyl-N-arylacetamides. Kolehmainen and co-workersreported the structural characterization of a series of a-phenylsulfonyl-W-arylacetamides of the type shown by 125 using multinuclear NMR methods. Among the NMR data employed by the authors were long-range HMBC spectral data. The... 

Arylacetamides undergo aerial oxidation to yield the corresponding a-keto amides without the need of a transition metal salt. The transformation is carried out in the presence of a base (CS2CO3) and Bu4NBr. Primary amines are converted into oximes in an aerobic oxidation employing l,l-diphenyl-2-picrylhydrazyl (1) and WO3/AI2O3 as catalyst. ... 

The two prominent 6,7-benzomorphan structural analogues are the racemate of ethylketazocine and bremazocine which predominantly exhibit kappa opioid receptor selectivity. These two compounds gained prominence as they were used initially to evaluate the kappa receptors but later on found to be possessing not-so-high a selectivity. However, quite recently, a variety arylacetamide ... 

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