1.3- Dipolar cycloadditions site selectivity

Cyclic imidate esters, 2-ethoxypyrrolin-5-one and 2-ethoxy-1II -indol-3-one, undergo 1,3-dipolar cycloaddition reactions with nitrile oxides, the reaction site being at the pyrroline C=N bond (317). Rigid and sterically congested pyrroline spiro compounds 148 demonstrate complete diastereofacial selection in site and regiospecific cycloaddition reactions with nitrile oxides to give products 149 (318). 

The 1,3-dipolar cycloaddition of imidazolinone 123 with ethyl m-4,4,4-trifluorocrotonate 124 provided, after 36 h at reflux, the regio- and stereoisomer 125 (90%), accompanied with traces of three other unidentified cycloadducts (10%) <2001JFC275>. Compound 125 was isolated in 70% yield (Scheme 15). The structures of the final product were elucidated by nuclear Overhauser effect (NOE) experiments. This high selectivity is the result of a preferred ///////-orientation of both ester and CF3 groups in the transition state and of an impeded ////////-approach of the CFj-substituted terminus of the alkene to the sterically hindered ct-site of 123. 

The intramolecular dipolar cycloaddition of a nitrone with an unactivated allene was also studied [76], Treatment of 5,6-heptadien-2-one with N-methylhydroxyl-amine in refluxing ethanol yielded allenyl nitrone 78, which cyclized with the terminal allenic C=C bond to give an unsaturated bicyclic isoxazolidine. On the other hand, the site selectivity decreased with an allenic ketone having a trimethylene tether. 

From the foregoing survey of heterocyclic hydrazonoyl halides, it appears that the main emphasis has been restricted to both their preparation and use as intermediates for further synthesis. Large areas of their chemistry, particularly regarding their physical and biological properties, remain to be developed. A deeper understanding of some aspects of their 1,3-dipolar cycloaddition reactions, such as regiochemistry and site selectivity in terms of the frontier molecular orbital method, is also needed. 

An interesting aspect of the type A heteropentalenes is the fact that each molecule is associated with two 1,3-dipolar fragments (45a<->45b) and, in principle, unsymmetrical systems can form two types of cycloadduct (46 or 47). In some cases the kinetically controlled product (46) is obtained at low temperature and the thermodynamically controlled product (47) is obtained at higher temperatures (see thieno[3,4-c]pyrroles, Chapter 3.18). For a given set of reaction conditions cycloaddition is usually site specific. For example, the non-classical thiophene derivatives of general structure (48) usually add across the thiocar-bonyl ylide fragment. This site selectivity is probably determined by the relative size of the HOMO coefficients at the alternative sites of addition. 

In this context, click chemistry has been explored as a method for rapid synthesis of compound libraries. In click chemistry, compounds are rapidly synthesized through heteroatom links by a set of powerful, highly reliable, and selective reactions, such as Huisgen s 1,3-dipolar cycloaddition reactions. Click chemistry uses chemical building blocks with built-in high-energy content to drive a spontaneous and irreversible linkage reaction with appropriate complementary sites in other blocks. 

The Site Selectivity of 1,3-Dipolar Cycloadditions. The site selectivity of 1,3-dipolar cycloadditions is the same as for the Diels-Alder reactions in Section 6.5.2.6. To give just two examples, the unsaturated ester 6.356 reacts with diazomethane at the 4,5-double bond, to give the adduct 6.357,871 and diazoacetic ester adds to the terminal double bond of 1-phenylbutadiene 6.358, giving the pyrazoline 6.359, with the product actually isolated after the loss of nitrogen being the corresponding cyclopropane.872... 

Ackerman and coworkers report a three-component one-pot cascade reaction to form annulated 1,2,3-triazoles. The reaction proceeds with a copper-catalyzed 1,3-dipolar cycloaddition followed by an intra-molecular C—H bond arylation, and utilises inexpensive Cul for the formation of the one C—C and three C—bonds in a site-selective manner (Scheme 7.12). 

Matsumoto K, IkemiY, KonishiH, ShiX-L, UchidaT(1988) Site selectivity in the 1,3-dipolar cycloaddition reaction of unsymmetric pyridinium bis(methoxycarbonyl)methylides with methyl propiolate. Heterocycles 11 2557-2562... 

---