Anilides, synthesis

The synthesis of amino acid anilides, phenylhydrazides, and other derivatives with papain has been extensively studied. The possibility that these reactions could provide a simple method for resolving racemic amino acids was the major reason for this interest. In addition to resolutions reported by Bergmann et al. (12,13,17), other amino acids have been studied, e.g., DL-3-fluorotyrosine (127), DL-tiyptophan (73), DL-methionine (46), oL-lysine (32), DL-alanine, DL-isoleucine, OL-norleucine, DL-valine, DL-serine, and DL-threonine (49). Doherty and Popenoe (49) have described some conditions required for resolution by anilide synthesis. 

Fox and his associates (54-58) have studied the effect of a number of factors on anilide synthesis by papain. They report that the optimal pH for anilide synthesis varies with the A-acyl amino acid used. The influence of the amino acid side chain influences the rate of anilide synthesis much as would be expected from the hydrolytic specificity of papain. 

IsoxazoIe-5-carboxyIic acid anilide, 3,4-diphenyI-synthesis, 6, 86 Isoxazolecarboxylic acids applications, 6, 128 IR spectra, 6, 5 potentiometry, 6, 11 reactions, 6, 52 synthesis, 6,27, 85-86 thermochemistry, 6, 10 IsoxazoIe-3,4-dicarboxyIic acid esters... 

The Knorr quinoline synthesis refers to the formation of a-hydroxyquinolines 4 from P-ketoesters 2 and aryl amines 1. The reaction usually requires heating well above 100°C. However, some cases do exist when the cyclization takes place in the presence of a catalytic amount of mineral acid at temperatures as low as -10 °C. The intermediate anilide 3 undergoes cyclization by dehydration with concentrated sulfuric acid. The reaction is conceptually close to the Doebner-Miller and Gould-Jacobs reactions. ... 

A variety of aryl systems have been explored as substrates in the Knorr quinoline synthesis. Most notable examples are included in the work of Knorr himself who has demonstrated the high compatibility of substituted anilines as nucleophilic participants in that reaction. In the case of heteroaromatic substrates however, the ease of cyclization is dependent on the nature and relative position of the substituents on the aromatic ring." For example, 3-aminopyridines do not participate in ring closure after forming the anilide... 

When bromoacetyl chloride is used instead of bromoacetic acid, the anilide 33 is formed at the first stage. Its subsequent cyclization also leads to 32. This approach to benzotellurazinone is similar to that developed for the synthesis of 2//-l,4-benzothiazin-3(4//)-ones (66CJC1247). Significantly, attempts to isolate the intermediate sulfonium salts analogous to 30 were unsuccessful. 

A synthesis of 4-methylquinolines 277 by the modified Fiiedlander reaction from ort/io-lithiated anilides 276 and 4-methoxybut-3-en-2-one (—20°C, THF, pentane, 2 h) in 14-17% yields (in the cyclization stage) has been described (91JOC7288). 

The oxidative formation of p-benzoquinones from anilides such as 7-108 was used for the synthesis of the core scaffold of the natural products elisabethin A (7-106) and pseudopterosin A aglycone (7-107) (Scheme 7.30). Exposure of anilide 7-108 to DMP [53] led to the formation of the o-imidoquinone 7-109, which underwent an intramolecular Diels-Alder reaction to give 7-110 in 28% yield after hydration. In a competitive pathway, the p-quinone 7-111 is also formed from 7-108, which on heating in toluene again underwent an intramolecular Diels-Alder reaction to give cycloadduct 7-112 in 25% overall yield. Hydrolysis of 7-112 furnished the carbocyclic skeleton 7-113 of elisabethin A (7-106). 

Amination of aromatic nitro compounds is a very important process in both industry and laboratory. A simple synthesis of 4-aminodiphenyl amine (4-ADPA) has been achieved by utilizing a nucleophilic aromatic substitution. 4-ADPA is a key intermediate in the rubber chemical family of antioxidants. By means of a nucleophibc attack of the anilide anion on a nitrobenzene, a o-complex is formed first, which is then converted into 4-nitrosodiphenylamine and 4-nitrodiphenylamine by intra- and intermolecular oxidation. Catalytic hydrogenation finally affords 4-ADPA. Azobenzene, which is formed as a by-product, can be hydrogenated to aniline and thus recycled into the process. Switching this new atom-economy route allows for a dramatic reduction of chemical waste (Scheme 9.9).73 The United States Environmental Protection Agency gave the Green Chemistry Award for this process in 1998.74... 

The condensation of anilides or enamides with nitriles was developed as a general method for the synthesis of pyrimidines or quinazolines such as 35 and 36 <06JACS 14254>. 

Na2CC>3), 25 °C, 24 h. Larock extended his work in several ways [302-305], particularly with regard to Pd-catalyzed cross-coupling of o-allylic and o-vinylic anilides with vinyl halides and triflates to produce 2-vinylindoles [303-305], an example of which is shown [305]. The related "Larock indole synthesis" is discussed separately in the next section. 

In 1892, the chemist Schopf, in an attempt to prepare 2-phenylamino-3-naph-thoic acid, developed a synthetic route leading to the anilide of 2-hydroxy-3-naph-thoic acid. His method continues to be used today, if only in a slightly modified form. He added phosphorus trichloride to a molten reaction mixture containing aniline and 2-hydroxy-3-naphthoic acid (beta-oxynaphthoic acid, also known as BONA) and received Naphthol AS in good yield. Modern processes differ from this principle only in terms of reaction control the synthesis is now carried out in the presence of organic solvents, such as aromatic hydrocarbons. 

The synthesis involves nitrosating the corresponding substituted acetoacetic anilide with sodium nitrite in acetic acid and subsequently, by adding hydroxyl-amine to the same reaction vessel, converting the compound to the oxime. Finally, complexation is achieved by means of a Ni(II) salt. 

FIGURE 8.4 Synthesis of anilides of A-protected glutamic acid by aminolysis of the anhydride in dimethylsulfoxide, which gives the a-isomers, and in benzene, which gives the a-isomers.18 X = H, Cl, OMe, N02. 

Synthesis of isatin 109 derivatives readily proceeds from anilide-derived oximes 108 by interaction with sulfuric acid (equation 46) ... 

An alternative to the synthesis of proteins by classical fragment synthesis in solution or by solid-phase synthesis on a support is the use of enzyme-catalyzed condensation of amino acids or peptides. This possibility was first demonstrated in 1938 91 with the synthesis of poorly soluble benzoyl-leucyl-leucine anilide by papain catalysis. After many years, this approach was extended to the preparation of peptide hormones such as Leu-enkephalin 92 and dynorphin(l -8).[93 This was made possible by the use of highly purified enzymes and by careful control of reaction conditions. The basic principles of protease-catalyzed peptide bond formation have been discussed.194 ... 

An unusual rearrangement following cyclization using a masked a-carbonyl equivalent, 2-anilino-2-ethoxy-3-oxothiobutanoic acid anilide 118, to form 6,7-disubstituted pteridine 119 by simply refluxing in ethanol for 3h was reported (Scheme 24) <2002JOC4526>. The synthesis of pyridopyrazine and related compounds using 39 was also discussed. 

An alternative but equally cumbersome synthesis utilizes the more accessible bis(2-carboxyphenyl)disulfide, easily prepared from anthranilic acid. Byconversion to the corresponding anilide, then by successive reduction with zinc dust and acetic acid (yielding 2-mercaptobenzoyl anilide) and lithium aluminum hydride, the aldehyde (6) is obtained in fair overall yield.Although... 

The acylation of amines on insoluble supports is one of the most thoroughly investigated reactions in solid-phase synthesis. The continuous optimization of peptide bond formation in recent decades has led to protocols that enable racemization-free, quantitative acylations of support-bound peptides with protected amino acids. In recent years, the range of amides available by solid-phase synthesis has expanded significantly to include, for example, N-alkylated peptides and anilides. New strategies for the preparation of amides, such as C-carbamoylations and the Ugi reaction, have also been successfully realized on insoluble supports. 

Processes include the Fischer indole synthesis from arylhydrazones and related sigmatropic syntheses, reductive evclizations of nitni compounds, the Madelung synthesis from anilides and related base-cululyxed condensations. and transition-metal catalyzed cyclizations,... 

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