Arylamides

Alkyl-2-arylthiazoles and 4,5-disubstituted-2-(p-aminophenyl thiazoles were simflarly prepared from arylamides and a-halomethyl-ketones in alcoholic (239, 392, 641, 792) or acetonic solution (638, 651). 

Hydroxy-2-Naphthalenecarboxylic Acid. l-Hydroxy-2-naphthoic acid is made similarly to the isomer (2-hydroxy-1-naphthoic acid) by reaction of dry sodium 1-naphthalenolate with CO2 in an autoclave at ca 125°C. It has been used in making triphenylmethane dyes and metalli able a2o dyes. Alkylamides and arylamides of l-hydroxy-2-naphthalenecarboxyhc acid are cyan couplers, ie, components used in indoaniline dye formation in color films (see Color PHOTOGRAPHY). 

These amides (45), which are of the Naphthol AS type, are important coupling components that are appHed to fiber, eg, cotton (qv). They then react with a dia2o component on the fiber to produce insoluble a2o dyes of high washfastness and lightfastness. A wide range of arylamides of... 

Cefazaflur (58) stands out among this group of analogues because it lacks an arylamide C-7 side chain (see cephacetri 1 e for another example).Cefazaflur (58) is synthesized by reaction of 3-(1-methyl-lB[-tetrazol-5-ylthiomethylene)-7-amino-cephem-4-carboxylic acid (56) with trifluoromethylthioacetyl chloride (57). ... 

Friedel-Crafts alkylations and acylations of N-arylamides also proceed normally. For example, benzoylation of acetanilide (iV-acetylaniline) under Friedel-Crafts conditions gives 4-aminobenzophenone in 80% yield after hydrolysis. 

Alkylnickel amido complexes ligated by bipyridine have been prepared that undergo reductive elimination of V-alkyl amines (Equation (54)).207,208 Unlike the phosphine-ligated palladium arylamides, these complexes underwent reductive elimination only after oxidation to nickel(III). Thermally induced reductive elimination of alkylamines from phosphine-ligated nickel complexes appears to occur after consumption of phosphine by arylazides 209... 

Recently, a method for synthesizing substituted pyridines incorporating 3-azadienynes as substrates in ruthenium-catalyzed cycloisomerizations was described <06JA4592>. This route is a two-step process that first converts readily available JV-vinyl or JV-arylamides (e.g., 26) to the corresponding C-silyl alkynyl imines (e.g., 27) and subsequent ruthenium-catalyzed protodesilylation and cycloisomerization results in the formation of the corresponding substituted pyridines (e.g., 28). 

Mercuration reactions provide a convenient approach to a broad range of arylmercury derivatives.82,83 This approach has been applied to a number of substrates, including phenols, indoles, phenylpyridines, and fV-arylamides.83 The products of these reactions as well as their conditions are summarized in Table 1.84 91 Other examples of such reactions include the mercuration of 2-(2 -naphthyl)pyridine (Equation (251)92 and terephthaldehyde (Equation (26))93 with Hg(OCOCF3)2 and Hg(C104)2, which afford 72 and 73, respectively. 

Chemical Properties of Ultimate Carcinogenic Metabolites of Arylamines and Arylamides... 

A number of arylamines and arylamides are carcinogenic in a variety of tissues of several species including the urinary bladder of man. These compounds undergo metabolic activation to ultimate carcinogens through a number of enzymatic and nonenzymatic pathways. In this review, these activation mechanisms are considered in detail and their relative contribution to the observed carcinogenicity of these compounds is discussed. 

N-Hydroxy arylamines readily form glucuronide conjugates, but in contrast to the N-hydroxy arylamides, these are N-glucuronides which are unreactive and stable at neutral pH. The N-glucuronides are readily transported to the lumens of the urinary bladder and intestine where they can be hydrolyzed to the free N-hydroxy arylamines by mildly acidic urine or by intestinal bacterial 3-glucuronidases (13,14). Non-enzymatic activation of N-hydroxy arylamines can occur in an acidic environment by protonation (15,16) of the N-hydroxy group (VIII) as well as by air oxidation (reviewed in 17) to a nitrosoarene (IX). 

The metabolic formation of N-sulfonyloxy-N-acetyl-2-aminofluorene (N-sulfonyloxy-AAF) and its observed electrophilic reactivity, provided the first evidence for the importance of enzymatic conjugation reactions in chemical carcinogenesis (23,24). This reaction was shown to be catalyzed by PAPS-dependent sulfotrans-ferases that are located predominantly in liver cytosol and has been subsequently demonstrated for N-hydroxy arylamide metabolites of several other carcinogens, including N-acetyl-4-aminobiphenyl (AABP), benzidine, N-acetyl-2-aminophenanthrene and phenacetin. 

Accordingly, the contribution of this metabolic activation pathway to the formation of covalently-bound adducts of arylamides with cellular proteins and nucleic acids has been the subject of numerous investigations, and has been reviewed extensively by Mulder (25). From these and more recent data (4,26,27) it is apparent, particularly in the case of N-hydroxy-AAF Tn-OH-AAF), that in vivo formation of reactive N-sulfonyloxy derivatives is primarily... 

Structural identification of the N-acetylated adducts found in vivo has shown that binding to protein or GSH involves predominantly ortho-ring substitution of the arylamide with the sulfur atom in methionine or cysteine, respectively. In contrast, arylamide binding to nucleic acids vivo involves both -substitution at the C-8 position of guanine and ortho-ring substitution with the exocyclic N2 atom of guanine (26,29-31,37,38). 

Although metabolically-formed N-sulfonyloxy arylamides are strong electrophiles, bind to cellular macromolecules, and have long been considered ultimate carcinogens, their precise role in aryl-... 

Figure 2. Reaction Mechanism for N-Sulfonyloxy Arylamides (I). Ac, acetyl RSCHs, methionine RSH, glutathione or cysteine RNH2, N2-guanine- and/or N6-adenine-nucleosides, -nucleotides, or -nucleic acids RCH, C8-guanine-nucleosides, -nucleotides, or -nucleic acids, or C7-AAF.

The role of N-acetoxy arylamides as metabolically formed ultimate carcinogens jji vivo also appears to be limited. Their enzymatic formation via peroxidation of N-hydroxy arylamides can be excluded since tissues containing high levels of peroxidases such as the rat mammary gland (83) and the dog urinary bladder (84) do not form acetylated carcinogen-DNA adducts in vivo (63). Their non-enzymatic formation by reaction of acetyl coenzyme A with N-hydroxy arylamides (6 ) cannot be excluded however, even if formed, their direct reaction with cellular DNA appears unlikely as treatment of cultured cells with synthetic N-acetoxy AAF (85,86) results primarily in deacetylated arylamine-DNA adducts, apparently due to rapid N-deacetylation to form the reactive N-acetoxy arylamine (V). 

N-Glucuronyloxy arylamides do not appear to be important in hepatocarcinogenesis as their increased metabolic formation does not result in increased hepatic macromolecular binding (4,25). 

Prolonged residence in the intestine or urinary bladder lumen could allow time for significant reaction with tissue components however, N-glucuronyloxy-AAF was only weakly carcinogenic at local subcutaneous sites of application (89). Enzymatic deacetylation to N-glucuronyloxy-AF has been detected in hepatic tissue but this activity in different species does not correlate with their relative susceptibility to AAF hepatocarcinogenesis (94). On the other hand, the alkaline pH-induced conversion to a reactive derivative may play an important role in urinary bladder carcinogenesis (87) by AAF and other arylamides in those species or individuals where normal urine pH is alkaline (e.g. normal rabbit urine pH is 8.5-9.0). 

In contrast to the reactivity of N-sulfonyloxy and N-acetoxy esters of arylamides and arylamines, the relative reactivity of protonated N-hydroxy arylamines with nucleophiles generally decreases in the order DNA > denatured DNA > rRNA = protein > tRNA nucleotides s nucleosides s methionine = GSH (2,13-17,30,36,40,127,129, 130). Furthermore, the rate of reaction with DNA was found to be not only first order with respect to N-hydroxy arylamine concentration, but also first order with respect to DNA concentration (127,129,131). These data suggested that the reaction mechanism was... 

---