Aromaticity 1,3-dipolar cycloaddition

The distinction between these two classes of reactions is semantic for the five-membered rings Diels-Alder reaction at the F/B positions in (269) (four atom fragment) is equivalent to 1,3-dipolar cycloaddition in (270) across the three-atom fragment, both providing the 47t-electron component of the cycloaddition. Oxazoles and isoxazoles and their polyaza analogues show reduced aromatic character and will undergo many cycloadditions, whereas fully nitrogenous azoles such as pyrazoles and imidazoles do not, except in certain isolated cases. 

In this section, reactivity studies will be emphasized while in those devoted to synthesis (Section 4.04.3) theoretical calculations on reactions leading to the formation of pyrazoles (mainly 1,3-dipolar cycloadditions) will be discussed. It should be emphasized that the theoretical treatment of reactivity is a very complicated problem and for this reason, most of the calculations have been carried out on aromatic compounds, as they are the easiest to handle. In general, solvents are not taken into account thus, at the best, the situation described theoretically corresponds to reactions taking place in the gas phase. 

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... 

Another example of a microwave-assisted 1,3-dipolar cycloaddition using azomethine ylides and a dipolarophile was the intramolecular reaction reported for the synthesis of hexahydrochromeno[4,3-fo]pyrrolidine 105 [70]. It was the first example of a solvent-free microwave-assisted intramoleciflar 1,3-dipolar cycloaddition of azomethine ylides, obtained from aromatic aldehyde 102 and IM-substituted glycinate 103 (Scheme 36). The dipole was generated in situ (independently from the presence of a base like TEA) and reacted directly with the dipolarophile present within the same molecifle. The intramolecu-... 

The nitrone arising from reaction between (Z)-19-nor-5,10-secosteroidal ketone 260 a and M-methylhydroxylamine hydrochloride undergoes transannu-lar 1,3-dipolar cycloaddition to give isoxazolidines 261 and 262 and an aromatic derivative 263 originating from 261 (Scheme 28). Corresponding reaction of 260b produces two types of structurally different isoxazolidines 264 and 265 as well as the dienone 266. 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

H(65)1889, 2005EJO3553>. Starting dihydro[l,2,4]triazolo[3, 4-4]benzo[l,2,4]triazines 482 readily react with aromatic aldehydes to yield iminium salts 483. These salts treated with a base (e.g., triethylamine) are deprotonated to reactive 1,3-dipolar azomethine imines 484. In contrast to related five-membered heterocycles, these compounds are relatively unstable on storage in the solid form and particularly in solution. Fortunately, this obstacle can be easily circumvented by their in situ preparation and subsequent 1,3-dipolar cycloaddition. These compounds can participate in 1,3-dipolar cycloadditions with both symmetric and nonsymmetric dipolarophiles to give the expected 1,3-cycloadducts in stereoselective manner. Selected examples are given in Scheme 82. 

The 1,3-dipolar cycloaddition of diazoalkanes 276 and nitrile oxides 279 to isothiazole dioxides 275 provides an easy entry into fused bicyclic isothiazole systems 277 and 280, respectively <06JHC1045>. The adducts from 4-bromoisothiazole (R1 = Br) are labile and undergo spontaneous debromination to form the aromatic bicyclic pyrazolo-isothiazoles 278... 

Microwave irradiation induces 1,3-dipolar cycloadditions of nitrones, such as 152, with aliphatic and aromatic nitriles in the absence of solvent. The products of these reactions are the corresponding 2,3-dihydro-l,2,4-oxadiazoles 156 (Scheme 9.48). The use of microwaves led to yields that were always higher than those obtained with classical heating, with the differences being more significant with the less reactive nitriles [99]. 

Diaz-Ortiz described the microwave-induced 1,3-dipolar cycloadditions of the me-sitonitrile oxide 10 with aliphatic and aromatic nitriles in solvent-free conditions [99]. The procedure allowed the corresponding heterocyclic adducts, the 1,2,4-oxadia-zoles 187, to be obtained in a domestic oven. The reaction times were shorter and the yields better than those seen with the classical homogeneous reactions (Scheme 9.57). 

Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

Hu and co-workers reported a facile synthesis of pyrrolo[2,l-n]phthalazine 205 by a 13-dipolar cycloaddition of phthalazium N-ylides generated from 203 with electron deficient alkenes to give 204, followed by treating 204 with tetrakispyridine cobalt(II) dichromate [Py4Co(HCr04)2, TPCD] to complete the aromatization <00JHC1165>. 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

Heterocycles Both non-aromatic unsaturated heterocycles and heteroaromatic compounds are able to play the role of ethene dipolarophiles in reactions with nitrile oxides. 1,3-Dipolar cycloadditions of various unsaturated oxygen heterocycles are well documented. Thus, 2-furonitrile oxide and its 5-substituted derivatives give isoxazoline adducts, for example, 90, with 2,3- and 2,5-dihydro-furan, 2,3-dihydropyran, l,3-dioxep-5-ene, its 2-methyl- and 2-phenyl-substituted derivatives, 5,6-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene, and 1,4-epoxy-l,4-dihydronaphthalene. Regio- and endo-exo stereoselectivities have also been determined (259). 

Cycloaddition reactions of nitrile oxides with 5-unsubstituted 1,4-dihydro-pyridine derivatives produced isoxazolo[5,4-Z>]pyridines in moderate to good yield. In each case examined, the reaction produced only a single isomer, the structure of which was assigned by NMR spectra and confirmed by X-ray diffraction analysis of 102 (270). A study of the cycloaddition behavior of substituted pyridazin-3-ones with aromatic nitrile oxides was carried out (271). Nitrile oxides undergo position and regioselective 1,3-dipolar cycloaddition to the 4,5-double bond of pyridazinone to afford 3a,7a-diliydroisoxazolo 4,5-<7]pyridazin-4-ones, for example, 103. 

I.3.4.2. Intermolecular Cycloaddition at C=X or X=Y Bonds Cycloaddition reactions of nitrile oxides to double bonds containing heteroatoms are well documented. In particular, there are several reviews concerning problems both of general (289) and individual aspects. They cover reactions of nitrile oxides with cumulene structures (290), stereo- and regiocontrol of 1,3-dipolar cycloadditions of imines and nitrile oxides by metal ions (291), cycloaddition reactions of o-benzoquinones (292, 293) and aromatic seleno aldehydes as dipolarophiles in reactions with nitrile oxides (294). 

A synthesis of novel spirodioxazole systems by the 1,3-dipolar cycloaddition reactions of 3,5-di-ferf-butyl-1,2-benzoquinone with aromatic nitrile oxides has been described (Scheme 1.31). Though yields are high (80%-100%), the regios-electivity is low, the regioisomer ratio 181 182 being dependent on the Ar nature (349). 

The 1,3-dipolar cycloaddition of a variety of aromatic and aliphatic nitrile oxides to 2.5-/ra//.v-2.5-diphenylpyrrolidine-derived acrylamide and cinnamamide 399, efficiently affords the corresponding 4,5-dihydroisoxazole-5-carboxamides 400 in highly regio- and stereoselectivity (Scheme 1.47). Acid hydrolysis of these products affords enantiopure 4,5-dihydroisoxazole-5-carboxylic acids 401 (443). 

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