Nitrogen basic hydrolysis

The 3-pyridylcarboxamide, prepared from the anhydride (Pyr, 99% yield), is cleaved (55-86% yield) by basic hydrolysis (0.5 M NaOH, rt) after quatemization of the pyridine nitrogen with methyl iodide. ... 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

Methylation of nitrogen at the 2 position also proves to be consistent with diuretic activity. Condensation of 160 with urea affords the heterocycle, 193. Treatment of this compound with methyl iodide and base effects alkylation on the more acidic ring nitrogen (194). Basic hydrolysis then gives the N-methylated aminosulfonamide (195). Condensation of this with chloroacetalde-... 

In a similar closure onto a nitrile, activation of the cyano functionality of intermediates 16 with TMSC1 (17) resulted in ring closure of the urea nitrogen to the nitrile carbon to form pyrimidones 18 following basic hydrolysis <00H347>. 

The bases adenine, guanine, and cytosine all contain exocyclic amino substituents that require protection, since these are potential nucleophiles. They are converted into amides that are stable to the other reagents used in the process, yet can be removed readily by basic hydrolysis. The most effective protecting groups have been found to be isobutyryl for the amino group of guanine, and benzoyl for adenine and cytosine. Thymine has no exocyclic nitrogen and does not need protection. 

The nitrogen-sulfur bond in reduced forms of 1,2,5-thiadiazole is much less stable than in the aromatic form. The reduced systems are readily hydrolytically desulfurized to the open-chain NCCN portion of the ring (80JPR273,690PP255, 69T4277). Mesoionic thiadiazoles are also sensitive to basic hydrolysis (81JCS(P1)1033). 

The three species are iso-electronic, the two ions being the analogs of carbon dioxide in the Nitrogen System of Compounds (p. 235). Neither of the ions is stable in acid solution, both being hydrolyzed to CO2 and the ammonium ion. The cyanate ion, however, may persist in moderately basic solutions and, indeed is sometimes prepared by basic hydrolysis of cyanogen by ammonia (in the presence of a metal ion which can remove the cyanide ion, also produced). 

The mechanism for basic hydrolysis begins with attack by hydroxide on the electrophilic carbon of the cyano group. Protonation gives the unstable enol tautomer of an amide. Removal of a proton from oxygen and reprotonation on nitrogen gives the amide. Further hydrolysis of the amide to the carboxylate salt involves the same base-promoted mechanism as that already discussed. 

The mechanism for acidic hydrolysis of a nitrile resembles the basic hydrolysis, except that the nitrile is first protonated, activating it toward attack by a weak nucleophile (water). Under acidic conditions, the proton transfer (tautomerism) involves protonation on nitrogen followed by deprotonation on oxygen. Propose a mechanism for the acid-catalyzed hydrolysis of benzonitrile to benzamide. 

Intramolecular cyclizations are not restricted to attack by a nucleophilic nitrogen (basic amino or acidic amido group). They can also be catalyzed by a nucleophilic oxygen as found in a carboxylate, phenolic, or alcoholic group. Illustration of the catalytic role of a carboxylate group can be found in hemiester prodrugs of phenol (taken as model compound) or paracetamol (Fig. 6 R = H or NHCOCH3, respectively). In addition to enzymatic hydrolysis, three mechanisms of chemical hydrolysis were seen, namely, acid-catalyzed, base-catalyzed, and an intramolecular nucleophilic attack. 

In the basic hydrolysis (21-20(a)), the step that drives the reaction to completion is the final step, the deprotonation of the carboxylic acid by the amide anion. In the acidic hydrolysis (21-20(b)), protonation of the amine by acid is exothermic and it prevents the reverse reaction by tying up the pair of electrons on the nitrogen so that the amine is no longer nucleophilic. 

It is cleaved by reduction (Hj/Pd-C, aq. EtOH, lOh, 98% yield Na/NHs, 1.5 h, 93% yield) and by basic hydrolysis (1N NaOH, dioxane, 20°C, 1 h, 93% yield). Photolysis can be used for deprotection of these esters after alkylation of the basic nitrogen. These salts are cleaved at >400 nm by sensitized photolysis in the presence of the radical scavenger cyclohexadiene (76-100% yield). Deprotection of the related phosphates has also been demonstrated in one case. The basic site in a picolyl ester allows its ready separation by extraction into an acidic medium. ... 

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