Regioselectivity cycloaddition

A systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was described. The studies permit the use of unsymmetrical dienophiles, dipolarophiles, and oxadiazoles as well as to control the cycloaddition regioselectivity and diastereoselectivity. The scope and utility of the reaction were defined <2006JA10589>. The tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction of 1,3,4-oxadiazole was applied to the syntheses of a series of natural products including a total synthesis of (-)- and ent-(+)-vindoline <2006JA10596>. 

The reactivity and regioselectivity of the cycloaddition of l-(A-phenacylidene)amino-1,2,3-triazoles with diphenyl nitrilimine (see Section 4.01.7.4) are examined on the basis of CNDO/2 calculations. The cycloaddition regioselectivity is HOMOjdipoie) controlled. The predominant orbital interaction shown in Figure 1 rationalizes the regioselective formation of 277-1,2,3-triazoles... 

Our initial interest in this area arose from the observation that the orbitals of the commonly accepted planar geometry of the parent nitrile ylide do not correctly account for the cycloaddition regioselectivities observed for these species. Thus, as shown by the examples in Fig. 14, the digonal carbon is the nucleophilic center of the molecules, whereas the HOMO of the planar species has the largest coefficient at the trigonal carbon, which should, therefore, be the more nucleophilic center of the molecule. However, full optimization of the geometry of nitrile ylide using the... 

Similarly, the noncomplementary C-2 - or C-4 addition of an electron-withdrawing substituent to the 1-oxa-1,3-butadiene serves to lower substantially the 1-oxa-1,3-butadiene lumo> accelerates its 4 ir participation in a LUMOdiene-controlled [4 + 2] cycloaddition reaction, maintains the endb-derived diastereoselectivity through the maintenance (C-4) or enforcement (C-2) of a large LUMO C-2 coefficient, and does not alter the observed [4 + 2] cycloaddition regioselectivity, although such substitution may decrease the magnitude of the difference between the O-l/C-4 LUMO coefficients (Table 5). 

A Benzenesulfony 1 aldimines have been shown to be more reactive than 7V-benzenesulfonyl ketimines (eq 2), and the complementary addition of a C-3 or the noncomplementary addition of C-2 and C-4 electron-withdrawing substituents substantially accelerate the Diels-Alder reaction and maintain the expected cycloaddition regioselectivity and exceptionally high endo diastere-oselectivity (eqs 3-5). ... 

In the oxazole system, the structural element of a bridged 2-aza-l,3-diene is present. Therefore, oxazoles are enabled to undergo Diels-Alder reactions with activated alkenes and alkynes. For example, acryhc acid (as an unsymmetrical activated dienophile) adds to the oxazole 13 to give the product 14 of a (4 + 2)-cycloaddition regioselectively. The Diels-Alder adduct 14 can be transformed to the pyridine derivative 15 by acid-catalyzed dehydration. 

Spiteri C, Moses JE (2010) Copper-catalyzed azide-alkyne cycloaddition regioselective synthesis of 1,4,5-trisubstituted 1,2,3-triazoles. Angew Chem Int Ed 49(l) 31-33 Agalave SG, Maujan SR, Pore VS (2011) Click chemistry 1,2,3-triazoles as pharmacophores. Chem Asian J 6(10) 2696-2718... 

However, its implementation in tandem intramolecular cycloadditions could expand the range of oxadiazoles that participate in the reaction cascade, extend their use to unsymmetrical dienophiles and oxadiazoles, control the cycloaddition regioselectivity, and increase the utility of tandem Diels Alder/l,3-dipolar cycloaddition reactions of such heterocyclic azadienes [196]. 

---