Acylamino groups, addition

Addition of an acyl group and an acylamino group to a double bond... 

Due to the important role of nitrogen functional groups, the addition reactions of an electrophilic selenium reagent and a nitrogen nucleophile to a carbon-carbon double bond represent a synthetically relevant process with potential practical applications. Among the reactions of this type which have been described already, perhaps the most important contribution is represented by the Ritter-type amide synthesis described by Toshimitsu and Uemura [48a, 48b]. The addition of a phenylselenyl and of an acylamino group to a mono or a 1,2-disubstituted olefin was accomplished by treating the olefin with PhSeCl in acetonitrile and water in the presence of trifluoromethanesulfonic acid. 

Keto-l,3-en-2-ols s. Tropolones Keto groups, addition of acylamino groups to —... 

A hypothesis about the role of the 6(7)p-acylamino side-chain conformation should thus take into account the full set of available facts. Moreover, the excellent activity of some of the new bicyclic P-lactams (see elsewhere in these volumes) demonstrates that the 6(7)-acylamino substituent is not always an essential structural ingredient for antibacterial activity. It is likely that the 6(7)-acylamino group serves as an additional handle by which the receptor sites may recognize and anchor the p-lactam antibiotic in the active site. This handle is essential for p-lactams with the reactivity of penicillins and cephalosporins, but is superfluous or even detrimental in more reactive p-lactams, as discussed later. Undoubtedly, a better appreciation of the conformation of the side chains will be possible after X-ray elucidation of the three-dimensional structures of the p-lactam-binding proteins of bacteria vide infra). 

The double bond of N-acylenamino acids and their esters represents the locus minoris resistentiae . As a result of conjugation with the carboxyl group, the double bond is a good acceptor for nucleophilic addends under basic catalysis. The acylamino group makes electrophilic additions possible. It is thus possible to obtain a- or P-mercapto a-amino acid derivatives by selecting the appropriate reaction conditions for the addition of mercaptans. 

Olefins with electron-donating substituents as the aUcoxy, acylamino, phenyl, or vinyl group can be coupled in methanol to give 1,4-dimethoxy dimers and/or dienes (Scheme 2). The first intermediate in this coupling reaction is a radical cation, which either by electrophilic addition to the olefin and subsequent le-oxidation (path A) [49] or by radical dimerization (path B) [50, 51] leads to a dimer dication that undergoes methanolysis or deprotonation. Representative examples of this coupling reaction are summarized in Table 7. 

Silyl-substituted diazoketones 29 cycloadd with aryl isocyanates to form 1,2,3-triazoles 194 (252) (Scheme 8.44). This reaction, which resembles the formation of 5-hydroxy-l,2,3-triazoles 190 in Scheme 8.43, has no analogy with other diazocarbonyl compounds. The beneficial effect of the silyl group in 29 can be seen from the fact that related diazomethyl-ketones do not react with phenyl isocyanate at 70 °C (252). Although the exact mechanistic details are unknown, one can speculate that the 2-siloxy-1-diazo-1-alkene isomer 30 [rather than 29 (see Section 8.1)] is involved in the cycloaddition step. With acyl isocyanates, diazoketones 29 cycloadd to give 5-acylamino-l,2,3-thiadiazoles 195 by addition across the C=S bond (252), in analogy with the behavior of diazomethyl-ketones and diazoacetates (5). 

Amides. Metal ions catalyze the hydrolysis of a variety of amides, including acylamino acids, dipeptides and tripeptides, and amino acid amides. In all these compounds it is possible for a metal ion to complex with one or more ligand groups, either amine or carboxylate ion functions, in addition to the amide group. Thus the structural prerequisites for the metal ion catalysis of amide hydrolysis are the same as those for ester hydrolysis. 

Anthrimide Carbazoles. Fast vat dyes are produced by carbazole ring closure from a,a-dianthraquinonylamines (anthrimides). The shade is determined by the number and position of the carbazole systems and by additional substituents, especially acylamino or alkoxyl groups. Anthraquinone carbazoles make it possible to dye cellulose fibers in level, very fast yellow, orange, brown, gray, and olive shades. However, this series lacks dyes with bright shades. 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

Approaches of type (i) include the Michael type addition of ester activated methylene groups to a,( -unsaturated carbonyls with subsequent cyclization to afford 277-pyran-2-ones <1984CHEC, 1996CHEC-II>. In this manner, 3-acylamino-277-pyran-2-ones are prepared by the reaction of (3-ethoxyvinyl ketones or P-(dimethylamino)vinyl ketones with iV-acylglycines (Scheme 138) <2005S1269, 2004HAC85>. 

The outcome of Grignard reactions on 5(4H)-oxazolones likewise depends on the nature of the substituent at C(4). The saturated azlactone (210) is converted by the action of phenylmagnesium bromide into the tertiary acylamino alcohol shown in equation (48) on the other hand, saturated azlactones are obtained by the action of alkyl Grignard reagents on (arylmethylene)oxazolones (equation 49). This type of oxazolone reacts with arylmag-nesium halides at the carbonyl group in the presence of copper chloride, however, the addition is directed to the methylene carbon atom. 

Diels-Alder reaction with ethyl atropate (2). The diene reacts with 2 to form a single cycloadduct 3. In contrast, when the —CH2CQ3 group is replaced by benzyl, the addition yields two crystalline adducts 4 and 5. In general l-(acylamino)-l,3-dienes show favored cndo-stereoselectivity, whereas l-(dialkylamino)-l,3-dienes show favored ejto-stereoselectivity. ... 

With the exception of glycine, all proteinogenic a-amino acids are chiral. The prevention of racemiza-tion in the case of the most commonly used a-protected amino acids is a prerequisite of successful peptide synthesis. W-acylamino acids might lose their stereochemistry according to the mechanism shown in Scheme 1. The proper choice of the protection group (e.g. urethane-derived), activation method and additives has to be made carefully. 

If the pyrido[2,3-c/]pyrimidine system contains a suitable leaving group in the 4-position, addition of hydroxide anion at C2 will lead to the cleavage of the C2 — C3 bond, yielding a 2-(acylamino)nicotinonitrile, as in the reaction of pyrido[2,3-d]pyrimidine-4-thiol (3) with chloroacetic acid and sodium carbonate.364... 

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