With acid-sensitive groups, synthesis

Instead of sodium nitrite, isoamyl nitrite is sometimes used as a nitrosating agent in synthesis of the benzotriazole ring. With this reagent, the reaction conditions are very mild allowing survival of acid sensitive groups. In an example of such a reaction, methyl 3,4-diamino-2-methoxybenzoate 1286 is treated with isoamyl nitrite at room temperature. The reaction is fast and provides methyl 4-methoxybenzotriazole-5-carboxylate 1287 in 62% yield, isolated by simple filtration off the precipitate (Equation 31) <2006JME4762>. 

K Barlos, O Chatzi, D Gatos, G Stavropoulos, T Tsegenidis. Fmoc-His(Mmt)-OH and Fmoc-His(Mtt)-OH. Two new histidine derivatives N""-protected with highly acid-sensitive groups. Preparation, properties and use in peptide synthesis, (dimeth-ylsilyldichloride) Tetrahedron Lett 32, 475, 1991. 

The examples discussed above constitute a selection of recent applications of the acid and basic hydrolysis of (3-lactams in synthesis. Hydrolysis and alcoholysis of (3-lactams can also be effected under roughly neutral reaction conditions when enzymes are the promoters [47]. The (3-lactamases catalyzed hydrolysis of (3-lactams is an efficient process for a broad spectrum of substrates, including those (3-lactams with base or acid sensitive groups [12-14]. This process proceeds through an acyl enzyme intermediate to give ring opened (3-amino acids. The class C (3-lactamases in particular, in Scheme 9, have the ability to catalyze the alcoholysis reaction and hence (3-amino esters are the products formed. 

Electrophilic aromatic substitution as a route to differentially substituted products is well established. The often forcing conditions, the incompatibility of this process with acid-sensitive functional groups, and the need for mild and selective syntheses have been the driving forces in the search for new methods of synthesis. A large range of methods has been developed over the past 20 years they include the trimerization of alkynes, the directed orfho-metallation, the benzannellation via metal carbenes, and transition metal-catalyzed carbon-carbon and carbon-heteroatom bond formation. Aromatic C-H activation, while still in its beginning stages, is another area of promise. 

This is a two-step sequence than can be used when R is an acid-sensitive group. The price of carrying out this methodology is the overall low minimum atom economy (AE) compared with the acid catalyzed option, which is a more direct synthesis. Note that in the second step, the water molecule added after the formation of the diazonium salt is not cancelled with the two water molecules formed prior since part of this water molecule ends up in the final product structure. In the first step, the water and sodium hydroxide molecules cancel each other out in the overall balanced chemical equation. 

Under certain circumstances, organochromium(ni) compoimds transfer their allaryl groups to aldehydes and, less frequently, to ketones. The particular selectivity and tolerance of this reaction make it particularly useful in organic synthesis. The use of these chromium reagents may be advantageous for use with acid-sensitive substrates, because of their reduced Lewis acidity relative to other transfer reagents [e.g., trichloromethyl-titanium(IV) or all[Pg.35]

Due to the strongly acidic conditions usually required for their activation, the ox-azoline method has not found broad application in the field of oligosaccharide synthesis. They are incompatible with acid-sensitive protecting groups and with poorly nucleophilic acceptors. Their employment seems to be restricted to reactive acceptors. Despite these severe limitations, some important examples of the application of the oxazoline method have been reported [136]. 

Thermolysis of 3-alkylsulflnyl-a-amino acid derivatives is an alternative reaction which has been applied to the synthesis of dehydroamino acid compounds 325, 326). Esters and peptides with dehydroalanine, dehydroaminobutyric acid, dehydrovaline and dehydrophenylalanine units have in many cases been obtained in excellent yields. The method is especially suitable for peptides with base sensitive groups. The elimination appears to take place with particular facility in compounds in which the amino acid unit bearing the sulfoxide group is present as a tertiary amide 326). Dehydrophenylalanine and dehydroaminobutyric acid derivatives are formed as mixtures of Z- and E-isomers on sulfoxide elimination. 

When a multistep synthesis is being undertaken with other sensitive functional groups present in the molecule, milder reagents and reaction conditions may be necessary. As a result, many alternative methods for effecting interconversion of the carboxylic acid derivatives have been developed and some of the most useful reactions are considered... 

Addition of a proton occurs to give the more-substituted carbocation, so addition is regioselective and in accord with Markovnikov s rule. A more detailed discussion of the reaction mechanism is given in Section 6.2 of Part A. Owing to the strongly acidic and rather vigorous conditions required to effect hydration of most alkenes, these conditions are applicable only to molecules that have no acid-sensitive functional groups. The reaction is occasionally applied to the synthesis of tertiary alcohols. 

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