1,3-dipolar cycloaddition 4+2 reactions

Dipolar cycloaddition reactions with azides, imines, and nitrile oxides afford synthetic routes to nitrogen-containing heterocycles (25—30). 

Most ozonolysis reaction products are postulated to form by the reaction of the 1,3-zwitterion with the extmded carbonyl compound in a 1,3-dipolar cycloaddition reaction to produce stable 1,2,4-trioxanes (ozonides) (17) as shown with itself (dimerization) to form cycHc diperoxides (4) or with protic solvents, such as alcohols, carboxyUc acids, etc, to form a-substituted alkyl hydroperoxides. The latter can form other peroxidic products, depending on reactants, reaction conditions, and solvent. 

Nitrile ylides derived from the photolysis of 1-azirines have also been found to undergo a novel intramolecular 1,1-cycloaddition reaction (75JA3862). Irradiation of (65) gave a 1 1 mixture of azabicyclohexenes (67) and (68). On further irradiation (67) was quantitatively isomerized to (68). Photolysis of (65) in the presence of excess dimethyl acetylenedicar-boxylate resulted in the 1,3-dipolar trapping of the normal nitrile ylide. Under these conditions, the formation of azabicyclohexenes (67) and (68) was entirely suppressed. The photoreaction of the closely related methyl-substituted azirine (65b) gave azabicyclohexene (68b) as the primary photoproduct. The formation of the thermodynamically less favored endo isomer, i.e. (68b), corresponds to a complete inversion of stereochemistry about the TT-system in the cycloaddition process. 

Oxazolium hydroxide, anhydro-5-hydroxy-aromaticity, 6, 184 cycloaddition reactions, 6, 209 dimerization, 6, 207 1,3-dipolar cycloaddition reactions with alkynes, 6, 210 electrophilic reactions, 6, 207 mesoionic reactions, 6, 188 reactions, 6, 206-211 synthesis, 6, 225-227... 

There is a large elass of reactions known as 1,3-dipolar cycloaddition reactions that are analogous to the Diels-Alder reaction in that they are coneerted [4jc -I- 2jc] eyeloaddi-tions. ° These reactions can be represented as in the following diagram. The entity a—b—c is called the 1,3-dipolar molecule and d—e is the dipolarophile. 

The stereochemistry of the 1,3-dipolar cycloaddition reaction is analogous to that of the Diels-Alder reaction and is a stereospecific syn addition. Diazomethane, for example, adds stereospecifically to the diesters 43 and 44 to yield the pyrazolines 45 and 46, respectively. 

The azomethine imines exhibit the typical cycloaddition behavior expected of 1,3-dipolar species [fSJ] Numerous [3+2] cycloaddition reactions have been performed [201 204] Tetracyanoethylene adds to azomethine imines across the nitnle function instead of the C=C double bond This reaction is a rare example of this type of periselectivity [208] (equation 47)... 

Azidofurazans and -furoxans undergo dipolar cycloaddition reactions with unsaturated compounds, in some cases regiospecifically. Thus, reaction of 3-amino-4-azidofurazan with l-morpholinyl-2-nitroethene (toluene, reflux, 70 hours) gives 4-nitro-l,2,3-triazole 204 in 87% yield (99MI1, 000KGS406). Cycloaddition of the same azide to alkynes was accomplished by formation of a mixture of position isomers 205 and 206. Regiospecific addition was observed only in singular cases... 

Similarly, the regiospecific 1,3-dipolar cycloaddition reaction of 1-methyl-1,2-dihydropyridines 41 with cyanogen azide (50a) and selected organic azides 50c and 50g afforded 2-methyl-2,7-diazabicyclo[4.1.0]hept-4-enes 57, which can be elaborated to 1-methyl-l,2,5,6-tetrahydropyridylidene-2-cyanamide (58) and 1-methyl-2-piperidylidenes 59a-d (85CJC2362). 

The cycloaddition reaction of 1,2,4-tiiazines 7V-oxides proceeds differently from the reaction of the corresponding 1,2,4-tiiazines. Thus the 1,2,4-triazine 4-oxide 55 acts only as a diene in the reaction with 1 -diethylaminopropyne to afford 2-methyl-4-(dimethylamino)pyrimidines 111. At the same time the 1,2,4-triazine 4-oxides 55 react with l-(dimethylamino)-l-ethoxyethylene by 1,3-dipolar cycloaddition to give 5-methyl-1,2,4-tiiazines 112 (78CB240). 

Gothelf presents in Chapter 6 a comprehensive review of metal-catalyzed 1,3-di-polar cycloaddition reactions, with the focus on the properties of different chiral Lewis-acid complexes. The general properties of a chiral aqua complex are presented in the next chapter by Kanamasa, who focuses on 1,3-dipolar cycloaddition reactions of nitrones, nitronates, and diazo compounds. The use of this complex as a highly efficient catalyst for carbo-Diels-Alder reactions and conjugate additions is also described. 

Asymmetric Metal-catalyzed 1,3-Dipolar Cycloaddition Reactions... 

The 1,3-dipoles consist of elements from main groups IV, V, and VI. The parent 1,3-dipoles consist of elements from the second row and the central atom of the dipole is limited to N or O [10]. Thus, a limited number of structures can be formed by permutations of N, C, and O. If higher row elements are excluded twelve allyl anion type and six propargyl/allenyl anion type 1,3-dipoles can be obtained. However, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions have only been explored for the five types of dipole shown in Scheme 6.2. 

Basic Aspects of Metal-catalyzed 1,3-Dipolar Cycloaddition Reactions 215 The normal electron-demand 1,3-dlpolar cycloaddition reaction... 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

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