Acetylene cycloaddition chemistry

Avalos and co-workers (220-228) extensively investigated the 1,3-dipolar cycloaddition chemistry of 2-aminothioisomiinchnones with both acetylenic and olefinic dipolarophiles. For example, sugar derivatives of the mesoionic imi-dazo[2,l-Z7]thiazolium-3-olate system react regioselectively with a variety of acetylenic dipolarophiles [DMAD, diethyl azodicarboxylate (DEAD), methyl propiolate, ethyl phenylpropiolate] to give the corresponding imidazo[l,2-a]pyr-idin-4-ones (e.g., 323) following sulfur extrusion from the not isolable cycloadducts (220). Similarly, these thioisomtinchnones react with diethyl azodicarboxylate and arylisocyanates in the expected fashion (221), and also with aryl aldehydes to form episulfides (222). 

A more recently published example of organic microwave synthesis under CF conditions is the 1,3-dipolar cycloaddition chemistry in the CEM CF Voyager system (Fig. 11). Savin and coworkers presented the cycloaddition of dimethyl acetylene dicarboxylate with benzyl azide in toluene, which was first carefully optimized with respect to solvent, temperature, and time under batch conditions. The best protocol was then translated to a CF procedure where a 0.33 M solution of both building blocks was pumped through a Kevlar-enforced Teflon coil (10 mL total capacity) heated in the single-mode reactor at 110 °C (10 min residence time) [66]. This method provided a 91% conversion to the desired triazole product (Scheme 12). 

Acetylenes with electron-withdrawing substituents such as Me02C = CC02Me or NCC s CCN have a rich cycloaddition chemistry. As alkynyliodonium salts are highly electron-deficient acetylenes they are expected to undergo a variety of electrocychc processes. 

Kappe and co-workers proposed an application of a microwave-assisted Huisgen 1,3-dipolar cycloaddition of terminal acetylenes and azides 70, imder Cu(I) catalysis, as an example of click chemistry to obtain a collection of... 

Scheme 7.1 Click chemistry synthesis of 1,4-disubstituted-l,2,3-triazoles by a 1,3-dipolar cycloaddition reaction of organic azides with terminal acetylenes.

Developments in aziridine chemistry, including the synthetic applications of their cycloadditions, have recently been reviewed by Lown and Matsumoto.35-37 Many investigators have added aziridines to acetylenic esters. Russian workers38 treated aziridine in the cold with various esters and then heated the mixtures to 40°-60° for 3 hours. They obtained 59% of compound 16 with EP, and 71 % of 17 with EPP, no stereochemistry being defined. Diethyl acetylenedicarboxylate gave 24% of the maleate 18 (R = Et) and 16% of the fumarate 19 (R = Et). 

The authors elaborated an innovative synthesis of the Taxane core based on an intramolecular Diels-Alder reaction as the key step. The TBDMS-protected cylohexenone-derived alcohol was converted into the corresponding nitrile intermediate in five steps by known synthetic manipulations (Scheme 43), mainly based on transmetallation protocols. The diene handle for the Diels-Alder reaction was then introduced following a simple but highly efficient four-step procedure. The dienophile for the cycloaddition, the terminal acetylene moiety, was incorporated via lithiation chemistry to furnish the substrate for the intramolecular Diels-Alder cyclization (Scheme 43). 

The formation of triazole rings by the reactions of azides and acetylenes was first described by Huisgen and coworkers [48,49] and has recently been promoted as dick chemistry by Sharpless et al. [50,51]. This versatile [3 + 2] dipolar cycloaddition proved to be useful for the synthesis of hyperbranched polytriazoles via 1,3-dipolar polycydoaddition of AB2-type monomers 28 and 29 (Scheme 14) [52], The monomers exhibited very high reactivity the... 

Katritzky, A.R. and Singh, S.K. 2002. Synthesis of c-carbamoyl-1,2,3-triazoles by microwave-induced 1,3-dipolar cycloaddition of organic azides to acetylenic amides. Journal of Organic Chemistry, 67 9077-79. 

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