Anilides, reactions hydrolysis

Presented in Fig. 8 are the data on the determination of the minimal amount of water required for a-chymotrypsin catalysis. The system CTAB-dimethyl sulfoxide/water-octane/chloroform was used as a reaction medium, and the volume ratio of water to dimethyl sulfoxide was varied from 0 to 0.001 [12,44]. It can be seen that in the totally dry system the reaction does not take place. Introduction of water activates the enzyme. Its full activation (defined by titration) occurs in the presence of just a few molecules of water (around 5) per enzyme molecule. The plateau in Fig. 8 is explained by the fact that the enzyme used is a hydrolase in low-water conditions acylation of the enzyme by the substrate occurs with quantitative formation of the acyl-enzyme. (Incidentally, it is a direct demonstration of acyl-enzyme formation in the reaction of chymotrypsin with an anilide substrate.) Hydrolysis of acyl-enzyme by water occurs at higher water concentrations, when, apparently, water appears as a reagent in a free state. 

Isocyanide reaction. Heat together gently 0 2 g. of the anilide, 3 ml. of ethanolic NaOH solution and i ml. of chloroform hydrolysis of the anilide occurs, and the odour of the isocyanide can be detected after about i minute s heating. [This test clearly differentiates an anilide of type R CONHC Hj from one of type R CO N(CH3)CeH5.]... 

Similar sulfenylation reactions of the 2-subsdtuted cyclic enamines of -keto carboxylic acid anilides are also possible, The trifluoromethanesulfenyl substitution takes place according to ring size Sulfenylation occurs at positions 2 and 5 with five-membered rings, at posibon 6 with six-membered tings, and at position 7 with seven-membered rings [5J (equation 4) (Table 1). Acid hydrolysis of the enamines proceeds readily to form the corresponding keto compounds. 

Enamines of cyclic ketones do not form cycloaddition products, but give the mono- or dicarboxanilides (110,111). Thus the enamine (113) on reaction with 1 equivalent of phenyl isocyanate gave 160. Treatment of 113 with 2 equivalents, or 160 with 1 equivalent, of phenyl isocyanate gave the 2,6-disubstituted product (161). Mild acid hydrolysis of 160 and 161 produced the corresponding cyclohexanone(2-mono- and 2,5-di)carbox-anilides (110). 

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). 

The nitrogen atoms of the twisted amides discussed on pages 107-108 are to a greater or lesser extent pyramidal, and incipient lone pairs electron density is thus available for reactions with electrophiles. The classic example is the cage lactam [57] first prepared by Pracejus (1959), which has an amide nitrogen with near normal amine basicity. Brown and coworkers have measured rates of alkaline hydrolysis of a series of anilides [58] and [59] with related structures and find that the rate increases with increasing divergence... 

The naphthalene-catalyzed (3-12%) lithiation of deprotonated chloro phenols and anilides 236 performed with n-butylUthium in THF at 0 or —78 °C, respectively, gave the corresponding functionalized aryllithium intermediates 237 which, by reaction with electrophiles and final hydrolysis, yielded the corresponding polyfunctionalized molecules 238 (Scheme 79) . 

The slow step of this process is often the initial nucleophilic displacement, and although the alkaline hydrolysis reaction (Y = HO ) is unique in that only a single displacement is involved, the step concerned is the same as the ratedetermining step for the reaction with many other nucleophiles. Kinetically, therefore, the reactions are comparable. A second important type of catalysis by nucleophilic reagents does not involve direct attack by the nucleophile on the ester. For example, the hydrolysis of ethyl dichloroacetate is catalyzed by aniline, and no anilide is produced in the reaction186, viz. 

Table 3.26 lists illustrative examples of cleavage reactions of support-bound N-aryl-carbamates, anilides, and /V-arylsulfonamidcs. /V-Arylcarbamatcs are more susceptible to attack by nucleophiles than /V-alkylcarbamates, and, if strong bases or nucleophiles are to be used in a reaction sequence, it might be a better choice to link the aniline to the support as an /V-bcnzyl derivative. Entry 7 (Table 3.26) is an example of a safety-catch linker for anilines, in which activation is achieved by enzymatic hydrolysis of a phenylacetamide to liberate a primary amine, which then cleaves the anilide. 

In Pschorr reactions involving anilides, amido groups must be protected to avoid the formation of triazinones122 iV-alkylation has commonly been employed, but the resulting iV-alkylphenanthridones are difficult to dealkylate. Similarly, protection by AT-alkylation has been employed in the case of the benzylamine (104 (R = Me).138 In a procedure designed to circumvent this difficulty, the N-sulfonylated diazonium chlorides, e.g., 104a-c, are decomposed catalytically acid hydrolysis, followed by oxidation, of the 5,6-dihydro derivative... 

Overman and Flippin utilized diethylaluminum amides for facile aminolysis of epoxides [71], The procedure involved treating a primary or secondary amine in CH2CI2 with EtsAl (1 equiv.) at room temperature for 30 min, then reaction with epoxide (1 equiv.) overnight. Hydrolysis of the resulting amino aluminate eventually afforded the /8-amino alcohol product in good yield. Aminolysis of cyclopentene oxide with diethylaluminum anilide is shown in Sch. 43 as a typical example. 

When the enzyme is used to catalyse the synthesis of a peptide bond, the solvent is either non-aqueous or contains only a low concentration of water. In addition, of course, an amino component such as an amino acid or peptide ester replaces the water in the second step. Obviously, the amino component must be unprotonated for reaction to succeed. Synthesis is favoured over hydrolysis of the resultant peptide because an amide is kinetically a much worse substrate for a proteinase than is an ester. The rapid acylation of a proteinase by an TV-protected amino acid or peptide aryl ester can be demonstrated experimentally using a stopped-flow apparatus with spectrophotometric facilities. A rapid burst of phenol is followed by steady-state release, showing that acylation of the enzyme is faster than hydrolysis of the acy-lated enzyme. No such burst is detectable if, for example, an TV-acylated amino acid anilide is used as substrate. In fact, acylation is the rate-determining step with amide substrates. 

In addition, since esterases and lipases are known sometimes to catalyze hydrolysis of amide bonds [59,60], we characterized the enzymes on p-nitro-anilide compounds to observe if there was any activity. As shown in Fig. 5, many of the enzymes do indeed have activity on these substrates and maybe useful in amide chemistry as well as the ester reactions mentioned earlier. This is an... 

Anilides substituted in 2- or 3-positions are monoarylated. 4-Substituted anilides can be either mono- or diarylated. For slower reactions or diarylation, use of silver trifluoroacetate instead of silver acetate is beneficial by increasing the reaction rate. The products can be deprotected by base hydrolysis to afford 2-aryl- or 2,6-diarylanilines. 

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