Acetylenes amidation

Triazoles have been obtained via microwave-assisted [3-i-2] cycloaddition, under solvent-free conditions [54], starting from organic azides and acetylenic amides at 55 °C for 30 min (Scheme 23). The complete conversion of the reagents into AT-substituted-1,2,3-triazoles 69 was achieved without decomposition and side products. A control reaction carried out at the same temperature in an oil bath did not give the cycHc products, not even after 24 h of reaction time. 

The acetylenic amide 294 is converted on irradiation in benzene into two oxidized dimers 295.243 A complex pathway involving a [ 4 + Kl cycloaddition followed by oxidation and photorearrangement has been proposed. 

The 1,3-dipolar cycloaddition of azides to alkynes is a versatile route to 1,2,3-tri-azoles. Different combinations of substituents on the azide and on the alkyne allow the preparation of diverse N-substitutcd 1,2,3-triazoles. Katritzky and Singh have described the synthesis of C-carbamoyl-1,2,3-triazoles by microwave-induced cydoaddition of benzyl azides to acetylenic amides (Scheme 6.220) [393]. Employing equimolar mixtures of the azide and alkyne under solvent-free conditions, the authors were able to achieve good to excellent isolated product yields by microwave heating at 55-85 °C for 30 min. In general, the triazole products were obtained as mixtures of regioisomers. Control experiments carried out under thermal (oil bath)... 

Scheme 6.220 1,3-Dipolar cycloaddition of benzyl azides with acetylenic amides.

In the case of acetylenic amides, the carbonyl oxygen atom turned out to be nucleoplilic enough to directly attack the coordinated triple bond, owing to the conjugation with the amide moiety. Thus, cGa-dialkyl substituted 2-ynylamides smoothly underwent oxidative cyclization-alkoxycarbonylation to afford new oxazoline derivatives in good yields (Eq. 44) [102,113]. 

The cis-fagaramide (J) was synthesized as outlined below. The required acetylenic acid (c) was prepared from piperonal (a) by the Corey s procedure.Treatment of piperonal with carbon tetrabromide, triphenylphosphine and zinc gave the bromo olefin (b) as an oil in 71% yield. The bromo olefin (b) was treated with 2 equivalents of n-butyl lithium followed by quenching with dry ice to give acetylenic acid (c) in 54% yield. Treatment of (c) with excess thionyl chloride without solvent at 50 followed by addition of isobutyl amine in benzene gave the acetylenic amide (d) as a viscous oil in 96% yield. Partial reduction of (d) gave cis-fagarmide (7 ) in 89% yield. 

As a part of research on the immnnosnppresant rapamycin it was found that acetylenic amides derived from diethylamine and proline gave the corresponding amide-diones with RuO /aq. Na(10 )/CCl -CH3CN [287]. 

Mono- and disubstituted acetylenic amides can be obtained in high yields by reacting metallated acetylenes with isocyanates and dialkylcarbamoyl chloride [95-98] ... 

The 1,3-dipolar cycloaddition of azides to acetylenic amides is particularly difficult under conventional thermal conditions and extended reaction times of 14 h to 1 week have been reported32,33. Katritzky reported a microwave-mediated solvent-free variant ofthis procedure to give N-substituted C-carbamoyl- 1,2,3-triazoles in good to excellent yields in only 30 min (Scheme 3.19)34. 

Katritzky, A.R. and Singh, S.K., Synthesis of C-carbamoyl- 1,2,3-triazoles by microwave-induced 1,3-dipolar cycloaddition of organic azides to acetylenic amides, ]. Org. Chem., 2002,67, 9077-9079. 

Undheim and Riege267 obtained 1 1 adducts from pyridine-2-thiones (60) and acetylenic amides, esters, and ketones. The reaction rate increases with increase in activation of the acetylenic bond by the adjacent carbonyl group and is affected by the pyridine 6-substituent, which may also affect the stereochemical course. Product-isomer ratios corresponding to kinetic control were obtained in chloroform. Amides gave E isomers, ketones gave Z, and esters a slight preponderance of the E isomers (61). Successive addition of n-butyllithium and DMAD to... 

Coppola, G. M. Damon, R. E. Acetylenic amides. 2. The generation and readions of dianions derived from 2-propynamides. 

Triazoles are generally prepared by the 1,3-dipolar cycloaddition of an alkyne with an azide at elevated temperatures. Thus, reaction of organic azides with acetylenic amides was significant only after 12 h refluxing in toluene. As a contrast, microwave dielectric heating at 55-85 °C under solvent-free conditions furnished the corresponding disubstituted... 

For the corresponding cyclization of acetylenic amides 418, Nagasaka etal.347,347a used a mixture of silver(i) triflate and lithium hexamethyldisilazide as the precatalyst. The process is probably initiated by the coordination of AgN(SiMe3)2 (generated in situ from AgOTf and LHMDS) to the triple bond, followed by nucleophilic attack of the lithium amide at the activated alkyne which affords (ZVy-alkylidene-y-butyrolactams 419 in high yields (Scheme 122). 

Reaction of Ta-alkyne complexes with R R2C=0. The Ta complexes formed from TaCls/Zn with unsymmetrical alkynes react with carbonyl compounds to form two rcgioisomcric allylic alcohols with a ratio depending on the substituents on the alkync (both steric and electronic effects) as well as the size of the substituents in the carbonyl group. The complexes from acetylenic esters react with carbonyl compounds mainly at the position or to the ester group, whereas complexes from acetylenic amides react mainly at the position fi to the amide. 

In the pepper alkaloid group, several new amides have been isolated from Achillea spp. One of them, from A, biebersteinil Afan, is the piperideide(19)Others include (20) (from A. ly caonica Boiss, et Heldr.), and the hitherto structurally unencountered acetylenic amides (21) and (22) (from A. spinulifolia Fenzl ex... 

The preparation of alkyl, alkenyl, and aryl derivatives of cyanoacetylene (1) poses no particular problems. In most cases a terminal acetylene is metalated or converted into an alkynyl Grignard reagent, and these intermediates are subsequently intercepted by a cyano source , which in most cases is either cyanogen chloride or bromide and sometimes cuprous cyanide or phenyl cyanate. Of course, dehydration of an acetylenic amide as described for the parent molecules is also possible and has occasionally been employed. 

The Huisgen 1,3-dipolar cycloaddition of azides to alkynes or nitriles as dipolaro-philes, resulting in 1,2,3-triazoles or tetrazoles, is one of the most powerful click reactions . A limitation of this approach, however, is the absence of regiospecificity normally found in thermal 1,3-cycloaddition of nonsymmetrical alkynes this leads to mixtures of the different possible regioisomers. In other reports, classical 1,3-dipolar cycloadditions of azides to metal acetylides, alkynic Grignard reagents, phosphonium salts and acetylenic amides have been described. Extended reaction times and high temperatures are required in most of the reactions, but they can also be performed more effectively with the aid of microwave irradiation. The main results reported are reviewed in this section. 

The amides 23, i.e., the products from the reaction of the anhydride (1) and the acetylenic amides 21 (see part 1), undergo cyclization to the derivatives of oxazoloquinazoline 275 (yields 31-50%) when treated with triphosgene in pyridine. The configuration of the initial amines 21 and amides 23 is retained [10],... 

Isobutylamine occurs as amides of various unsaturated aliphatic and aromatic organic acids in the Asteraceae (along with acetylenic amides), Piperaceae, and Rutaceae. Several... 

Isolation.- The cimides (84) - (86) occur in Leuooyolus formosus and (87) occurs in Achillea orithmifolia, The related acetylenic amides from A. tomentosa have already been described. The olefinic... 

Unsaturated Amides. - In further examples of conjugate additions to unsaturated amides, various stannyl copper species have been found to add to acetylenic amides (428) to give either (E)- (429) or ( )-3 Stannyl amides, depending on the reaction conditions. 

N-silylated a-acetylenic amides, esters and ketones undergo Cu assisted electrophilic... 

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