Arylacetamides

The hydrolysis of arylacetonitriles may be arrest at the arylacetamide stage by treatment with concentrated hydrochloric acid at about 40° thus benzyl cyanide yields phenylacetamlde ... 

By the action of concentrated hydrochloric acid at about 40° upon aryl-acetonitriles hydrolysis is arrested at the arylacetamide stage (see Section IV, 160 for the preparation of phenylacetamide by this method) ... 

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. 

Rhone-Poulenc have synthesized some kappa agonists which are of chemical interest because the arylacetamide fragment, which characterizes all of... 

The reaction of arylacetamides with ethyl phenylpropiolate gives 4,5-diaryl-l,5-dihydro-2//,67/-pyridine-2,6-diones (197). - It has been suggested that the pyridinediones in these reactions are formed through the initial addition of either the amide anion (195) or the carbanion (196), generated under basic conditions, to ethyl phenylpropiolate (Scheme 30). 

The following arylacetamides have been prepared from the corresponding nitriles by the same method in the indicated yields 4 -methylphenylacetamide (70%), -isopropylphenylacet-amide (90%), 1-naphthylacetamide (54%), 5,6,7,8-tetrahydro-2-naphthylacetamide (90%), />-methoxyphenyl acetamide (76%), 3,4-dimethoxyphenylacetamide (82%), and 2,3-dimethoxyphenyl-acetamide (91%). Only in the cases of the alkoxy-substituted nitriles are the resulting amides soluble in the reaction mixture the other nitriles do not dissolve completely at any time during the reaction. 

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... 

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>. 

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... 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

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,... 

HZ2 (163), which is structurally unrelated to the arylacetamide K-selective agonists, ex-... 

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