Amides, from acid derivatives alkynes

Carboxylic acids and their derivatives like esters, amides, anhydrides, and acyl halides are formally synthesized from olefins, carbon monoxide, and compounds represented by Nu-H such as H2O, ROH, RNH2, RCOOH (Equations (4) and (5)). Alkynes also react under similar conditions to afford the corresponding unsaturated carboxylic acid derivatives. These reactions have been named hydrocarboxylation, hydroalkoxycarbonylation, and hydroaminocarbonylation. 

As with carboxylic acids obtained by palladium hydroxycarbonylation, their derivatives esters, amides, anhydrides and acyl halides are synthesized from alkenes, CO and HX (X = OR, NR2 etc.). The Pd-catalyzed methoxycarbonylation is one of the most studied reactions among this type of catalyzed carbonylations and has been reviewed and included in reports of homogeneous catalysis.625, 26 The methoxycarbonylation has been applied to many different substrates to obtain intermediates in organic syntheses as well as specific products. For instance, the reaction has been applied for methoxycarbonylation of alkynes666 Highly efficient homogeneous Pd cationic catalysts have been reported and the methoxycarbonylation of alkynes has been used to develop economically attractive and environmentally benign process for the production of methyl... 

N-Substituted amides derived from 2-chloro- or4-chloronicotinic acid react with CH-acidic nitriles in the presence of base to yield amino derivatives of [l,6]naphthytid-5(6//)-ones and [2,7]naphthyrid-l(2//)-ones <1997JHC397>. 3-(l-Alkylamino)pyridines react with electron-deficient alkynes (acetylene dicatboxylates) in the presence of acid to give l,2-dihydro[2,7]naphthyridine-3,4-dicarboxylates in up to 72% yield compounds unsubstituted at C-1 were readily oxidized with potassium permanganate to naphthyridine-l-ones <2005TL3953>. 

For the final part (Scheme 5.3), the 20-carbon chain of fumonisin Bj was coupled from the Uthium acetylide derived from 273 and the Weinreb amide 279 (233). After enantioselective reduction of the alkynyl ketone 281 (234, 235), the C-10 stereochemistiy was set, followed by benzyl ether formation and acid-catalyzed acetonide removal, to provide diol 282 (236). Using tricarballylic acid dibenzyl ester, the two hydroxy groups were esterified (237) and the hydrogenation of the azide, the alkyne, and the benzylic ethers led to the target product, fumonisin Bj (249). The spectroscopic analysis matched with those of commercial fumonisin Bj and further experiments on the synthetic material showed inhibitoiy activity on sphingoUpid biosynthesis. 

In contrast to the common methods described above, no sophisticated or powerful dehydration reagent is needed and the reaction can easily be carried out on a large scale. A reaction mechanism has been suggested, in which the aldehyde serves as a relay for the water transfer from the amide to the acetonitrile solvent. The aldehyde may be varied, but formic acid is essential for the reaction. Alkyne derivatives decompose under the reaction conditions, and both THP ethers and TBDMS groups are unstable. 

A plausible mechanism was proposed in Scheme 7.10. Firstly, 2- alkynyl-benzaldehydes 20 could be easily obtained via a Sonogashira reaction of 2-bromobenzaldehyde with alkyne. After condensation with sulfonohydrazide, N -(2-alk50iylbenzylidene)hydrazide I would be afforded. Subsequently, the 6-endo-cyclization would occur to generate the isoquinolinium-2-yl amide II in the presence of suitable Lewis acid. In this step, the formation of a p-complex via coordination of the alkynyl moiety of 20 to the Lewis acid would be involved, thus activating the triple bond for further cyclization. Meanwhile, die in situ formed enolate (derived from ketone or aldehyde in the presence of base) would attack the isoquinolinium-2-yl amide II to produce intermediate III. Subsequent intramolecular condensation and aromatization would give rise to the desired product 22. 

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