Group 14 amides transformations

With 1-hydroxytryptophan derivatives, similar substituent effects are observed (99H2815). In order to realize better yields of 5-substituted tryptophans, car-boxy and amino groups are transformed to ester and/or amide groups, choosing the 1-methoxy moiety as a leaving group. As a result, ( )-Ab-acetyl-5-chlorotryptophan methyl ester (219, 52%) is obtained together with 220 (7%) from ( )-218 by the reaction with aqueous HCl (Scheme 32). ( )-5-Bromo-Ab-methoxycarbonyltryptophan methylamide (222, 50%) becomes readily available... 

This pronucleophile serves as the equivalent of the enolate of a methyl ketone, because the methoxycarbonyl group can be removed selectively by saponification/ decarboxylation and the resultant Weinreb amide transformed into a ketone. An example is described in Section 9.6. 

Reductive gem-dimethylation. An amide carbonyl group is transformed into two methyl substituents by MeMgBr-TiCl (ZrCl can be used also). 

Activation of a-hydroxy acids. The derivatization is complete at room temperature. When an amine is present, the carboxyl group is transformed into an amide. 

An early synthesis, published in 1983 and 1984 [83], requires three steps from 2-chloro-N-(2,4-dichlorophenyl)acetamide (Scheme 17.17). First, the amide group is transformed into imidoyl chloride with phosphorus pentachloride, followed by displacement of the two non-aromatic chlorine atoms by two equivalents of the potassium salt of 1,2,4-triazole. The triazolyl group borne by the imino bond being the best leaving group is replaced when reacted with a good nucleophile such as (4-chlorophenyl)methanethiol. The stereochemistry (E or Z) of the double bond is not stated in the literature. 

Another approach is the resolution of an enantiomeric mixture with a structurally similar resolving agent. It is the situation when one of the enantiomers of the racemic compwimd is transformed (with a minimal chemical transformation) into a reagent able to form diastereoisomeric salt with the initial racemic compound. It can be done if the aminoacid is N-acylated and one of the pure enantiomers is esterified, or if its carboxylic group is transformed into an amide, or changed with methyl group, respectively. 

Tomalia presented the synthesis of dendrimers as Starburst polymers, which consisted of poly(amide-amine)s as shown in Scheme 1 [2]. The core molecule in this case was ammonia, and the building block was methylacrylate. First, ammonia reacted with methylacrylate by a Michael-type addition. The obtained ester-terminated molecule was treated with a large excess amount of ethylene-diamine to form amino groups at the terminal positions (generation 0, GO). In this reaction, the methylester is the protected form of the amine, and the treatment with ethylenediamine (ester-amide transformation) corresponds to the deprotection of the ester function. Treatment of this amine-terminated molecule again with methylacrylate results in the formation of another terminal methyl-ester group. The molecule can be extended by repeating these operations. 

The chemistry of carboxylic acids is the central theme of this chapter The impor tance of carboxylic acids is magnified when we realize that they are the parent com pounds of a large group of derivatives that includes acyl chlorides acid anhydrides esters and amides Those classes of compounds will be discussed m Chapter 20 Together this chapter and the next tell the story of some of the most fundamental struc tural types and functional group transformations m organic and biological chemistry... 

Methylpyridazine can be oxidized with selenium dioxide to give 3-formylpyridazine, and methyl groups attached to any position in pyridazine N-oxides are transformed with pentyl nitrite in the presence of sodium amide in liquid ammonia into the corresponding... 

For synthetic purposes, aldol-rype condensations of aldehydes with esters or amides are potentially of great utility because the carbonyl group is easily transformed either by further additions or by oxidation or reduction. Deprotonation of an ester [7, 19, 20] or amide of fluoroacetic acid [9, 27] has led to aldol condensations in high yields (equation 17) (Table 7)... 

It is neeessary to emphasize that the direet amination of the methyl group at position 5 of pyrazoles is impossible. Neither 1,3,5-tiimethyl- nor4-ethynyl-l,3,5-trimethylpyrazole undergoes sueh transformations under the reaetion eonditions and starting materials are reeovered nearly quantitatively. Moreover, 4-bromo-ethynyl-l,3,5-trlmethyl- and 4-iodoethynyl-l,3,5-trimethylpyrazole with sodium amide in ammonia exehange the halogen for metal almost quantitatively and in this respeet are similar to phenylehloroaeetylene (Seheme 102). 

Amide-induced pyridine-pyrimidine transformation is also reported with 2-bromo-l, 5-naphthyridine. 2-Methyl-4-amino-l, 3,5-triazanaphtha-lene is obtained, together with its 4-amino derivative The presence of the amino group at position 4 is certainly due to a SnH amino-dehydrogenation in preformed 2-methyl-l,3,5-triazanaphthalene (63RTC997, 73RC459, 94MI1). 

Tiazofurine (142) is an antimetabolite with antineoplastic activity. It preferentially affects leukemic lymphocytes over normal cells due to selective activation by formation of its adenine dinucleotide by transformed cells. Of the syntheses available, one starts by conversion of iniidate 138 to methyl 2,5-anhydroallonothioate (139). Next, condensation with ethyl 2-amino-2-cyanoac-etate leads to the thioamide which undergoes thiol addition to the nitrile function to produce the amminothiazolecarboxyester system of 140 directly. Sodium nitrite in aqueous hypophosphorus acid eliminates the superfluous amino group via the diazonium transformation to give 141. This synthesis of tiazofurine (142) concludes by ester amide exchange in methanolic ammonia [48]. 

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