1,3-Dipolarophiles

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

It was found that the reaction of 5-acetoxy- and 5-benzoyloxy-2(5//)-furanones 174 with aryl nitrile oxides afforded only one cycloadduct, the condensed isox-azoline 233 (88TL5317). In principle, there are four possible cycloadducts 233 and 234 resulting from the anti approach of the 1,3-dipolarophile to the acetoxy group (with exo configuration of the acetoxy substituent), and two further isomers... 

The intramolecular cycloaddition of munchnone intermediates (derived from the cyclodehydration of A-acyl amino acids) with 1,3-dipolarophiles was employed to construct the mitomycin skeleton. Thus, heating alkynyl acids 23 with acetic anhydride forms the intermediates 24 which undergo cyclization with loss of carbon dioxide to afford the 4-oxo-tetrahydroindoles 25 <96TL2887>... 

Thermolysis of 16e,f in either solution or gas phase (150-350 °C) gave deuteriated ethylenes (i.e. 40e from 16e and 41f from 16f) with about 95% retention of stereochemis-try ". Similarly, pyrolysis of the stereoisomeric 2,3-diphenylthiirane oxides 16g,h proceeded smoothly to yield stilbenes and sulfur monoxide in more than 70% yield . The extrusion of SO from the trans-isomer proceeds almost stereospecifically, while that from the cis-isomer occurs with complete loss of stereochemistry. This indicates the intervention of a stepwise mechanism, and not a symmetry-allowed nonlinear chelatropic reaction . Based on the fact that all attempts to trap the intermediate with 1,3-dipolarophiles were in vain, whereas a 1 1 adduct was obtained in good yield (about 60%) with the carbon radical scavenger di-p-anisyl thioketone, a mechanistic scheme as depicted in equation 10 has been proposed . Although the radical intermediates are capable of internal rotation about the carbon-carbon bond, for the 2,3-diphenyl case (i.e. 16g,h), the rotation would be... 

Wiberg had also described a number of [2+3] cycloadditions of his silenes with 1,3-dipolarophiles such as N20, diazo compounds, and azides.98... 

This has been mentioned at various points in this paper and may involve either a direct acid-base reaction of nitrene and nucleophile or, in some instances, reaction of the nitrene precursor with the nucleophile (or 1,3-dipolarophile) followed by loss of nitrogen. For example, the reaction of benzenesulphonyl azide with pyridine to give 31 (Ar=Ph) 69> could either involve a free nitrene or a concerted process in which the lone pair on the pyridine nitrogen atom assists the elimination of molecular nitrogen. That some free nitrene can be involved in these reactions is clear from the isolation of some 3-benzenesulphonamido-2,6-lutidine... 

Et2 group in 2-670. Since 2-670 contains both, a 1,3-dipole as well as a 1,3-dipolarophile moiety, it immediately undergoes a 1,3-dipolar cycloaddition to form the heterocyclic compound 2-671. 

Several other groups have employed a similar approach. Muthusamy and coworkers prepared cyclooctanoid ring systems such as 6/2-14 and 6/2-15, respectively, starting from 6/2-12 either with N-phenylmaleimide or dimethyl ethynedi-carboxylate as 1,3-dipolarophiles via the dipole 6/2-13 (Scheme 6/2.2) [190]. 

These authors also prepared novel epoxy-bridged cyclooxaalkanones in this process, the carbonyl group always acts as 1,3-dipolarophile, even if one employs ct,(3-unsaturated aldehydes. Thus, reaction of 6/2-16 with aliphatic or aromatic aldehydes 6/2-17 in the presence of catalytic amounts of rhodium acetate gave 6/2-18, regioselectively. With the a, 3-unsaturated aldehydes 6/2-20, only cycloadducts 6/2-21 were obtained using the diazo compound 6/2-19 as substrate (Scheme 6/2.3) [191]. 

Conjugated heteropentalene mesomeric betaines are electron rich with high-energy HOMO and can be regarded as masked 1,3-dipolarophiles. Their main reactions are electrophilic substitution and cycloaddition reactions with electron-deficient 1,3-dipolarophiles, both were duly discussed in CHEC-II(1996) <1996CHEC-II(8)747>. 

Thermolysis of 6-substituted l,5-diazabicyclo[3.1.0]hexanes 326, easily available from 325, leads to a diaziridine ring opening and to the intermediate formation of labile azomethine imines 327. These compounds can be stabilized by a proton shift to form 1-substituted 2-pyrazolines 328. However, when the thermolysis is carried out in the presence of a 1,3-dipolarophile, the corresponding products of dipolar cycloaddition can be obtained. For example, iV-arylmaleimides provide mixtures of the major trans- and minor air-products 329 and 330, respectively (Scheme 47) C1999RJO110, 2001RJ0841, 2003RJ01338, 2004RJ067>. 

Arylethynyl(phenyl)iodonium salts, RC=CI+Ph 4-MeC6H4S03-, react as 1,3-dipolarophiles with nitrile oxides R CNO to afford phenyl(substituted isox-azolyl)iodonium salts 210, which give iodoisoxazoles on reaction with nucleophiles. The crystal structure of 210 (R = Ph, R1 = mesityl) has been determined (369). 

Nitrilium salts are more reactive 1,3-dipolarophiles than nitriles. With stable nitrile oxides, oxadiazolium salts (228) are obtained (Equation (38)). With unstable nitrile oxides the cycloaddition... 

Mesoionic 4-amino-l,2,3,5-thiatriazoles constitute the only class of mesoionic 1,2,3,5-thiatriazoles known. They are prepared by the reaction of l-amino-l-methyl-3-phenylguanidine with approximately 2 equivalents of thionyl chloride with pyridine as solvent (88ACS(B)63>. They are obtained as the yellow 1 1 pyridine complexes (17). The dark-violet mesoionic 1,2,3,5-thiatriazole (18) was liberated on treatment with aqueous potassium carbonate (Scheme 3). The structure is established on the basis of elemental analysis and spectroscopic data. In particular, the IR spectrum is devoid of NH absorptions. Compound (18) exhibits a long-wavelength absorption at 463 nm in methanol. When mixed with an equivalent amount of pyridinium chloride, complex (17) is formed and the absorption shifts to 350 mn. The mesoionic thiatriazoles are sensitive towards mineral acids and aqueous base and although reaction takes place with 1,3-dipolarophiles such as dimethyl acetylene-dicarboxylate, a mixture of products were obtained which were not identified. 

The meso-ionic 1,3-oxazol-S-ones show an incredible array of cycloaddition reactions. Reference has already been made to the cycloaddition reactions of the derivative 50, which are interpreted as involving cycloaddition to the valence tautomer 51. In addition, an extremely comprehensive study of the 1,3-dipolar cycloaddition reactions of meso-ionic l,3-oxazol-5-ones (66) has been undertaken by Huisgen and his co-workers. The 1,3-dipolarophiles that have been examined include alkenes, alkynes, aldehydes, a-keto esters, a-diketones, thiobenzophenone, thiono esters, carbon oxysulfide, carbon disulfide, nitriles, nitro-, nitroso-, and azo-compounds, and cyclopropane and cyclobutene derivatives. In these reactions the l,3-oxazol-5-ones (66)... 

The meso-ionic l,3-dithiol-4-ones (134) participate - in 1,3-dipolar cycloaddition reactions giving adducts of the general type 136. They show a remarkable degree of reactivity toward simple alkenes including tetramethylethylene, cyclopentene, norbomene, and norbor-nadiene as well as toward the more reactive 1,3-dipolarophilic olefins dimethyl maleate, dimethyl fumarate, methyl cinnamate, diben-zoylethylene, A -phenylmaleimide, and acenaphthylene. Alkynes such as dimethyl acetylenedicarboxylate also add to meso-ionic 1,3-dithiol-4-ones (134), but the intermediate cycloadducts are not isolable they eliminate carbonyl sulfide and yield thiophenes (137) directly. - ... 

Photochemical cycloaddition reactions between sydnones (1) and 1,3-dipolarophiles take place to give products which are different from, but isomeric with, the thermal 1,3-dipolar cycloaddition products. These results are directly interpreted in terms of reactions between the 1,3-dipolarophiles and Ae nit mine (316). The photochemical reactions between sydnones and the following 1,3-dipolarophiles have been reported dicyclopentadiene, dimethyl acetylene dicarboxylate, dimethyl maleate, dimethyl fumarate, indene, carbon dioxide, and carbon disulfide. ... 

The formation of various 1 1 adducts from dehydrodithizone 413, R = R = Ph, and various 1,3-dipolarophiles has been reported. Thus, dimethyl acetylenedicarboxylate yields 419, X = COOMe, tetra-cyanoethylene yields 420, and e oxycarbonylmethylenetriphenylphos-phorane yields the betaine 421. These transformations have been considered as 1,3-dipolar cycloaddition reactions of a novel type. It seems to us rather unlikely that these transformations are concerted 1,3-dipolar cycloadditions the alternative that they are reactions involving dipolar intermediates (e.g., 422, 423, and 424) should also be considered. The... 

The ring fused pyrroles 480 have been prepared by in situ trapping of the meso-ionic l,3-oxazol-5-ones (479) with alkynes. This 1,3-dipolar cycloaddition was found to be regiospecific when phenyl acetylene was used as 1,3-dipolarophile, the only products being 480, R = H or MeO, R = Ph, R2 =... 

A full account of the preparation and 1,3-dipolar cycloadditions of the meso-ionic l,3-thiazol-4-ones (114) has now been published. A detailed chemical and spectroscopic study of the stereochemistry of the 1 1 adducts of the l,3-thiazol-4-ones (114) with olefinic 1,3-dipolarophiles has been reported. ... 

In CHEC-II(1996) <1996CHEC-II(6)1> several examples of cycloaddition reactions of 1,3-dipoles to the 1,3-dipolarophilic 4,5-double bond of pyridazin-3(2//)-ones have been discussed. Only two examples of 1,3-dipolar... 

In the examples presented in CHEC-II(1996) in which a pyridazin-3(2//)-one is the 1,3-dipolarophile, two types of 1,3-dipoles are used nitrile oxides and diazoalkanes. Two other 1,3-dipoles have to be mentioned now. The 1,3-dipolar cycloaddition of the azomethine ylide 95 generated in situ by thermal ring opening of dimethyl trans- -(A-methoxyphenyl)aziridine-2,3-dicarboxylate 94 to some 4- or 5-substituted 2-methylpyridazin-3(2//)-ones has been... 

Mangalagiu studied the regioselectivity of the 1,3-dipolar cycloaddition of several pyridazinium methylides 105 to ethyl acrylate, ethyl propiolate, and acrylonitrile. The reaction is HOMO controlled from ylides and only one regioisomer 106 (major isomer as and minor isomer trans) or 107 is formed, namely the one in which the ylide carbanion makes a new bond with the most electrophilic carbon of the 1,3-dipolarophile. In some cases oxidation of 106 to 107 is observed in the reaction mixture in contact with the air (Scheme 23), which can be avoided by working in N2 atmosphere <1996T8853, 1997ACS927, 1999EJO3501>. 

Acetyl-2(3//)-oxazolone 84 serves as a good 1,3-dipolarophile in the [3+2] cycloaddition to A-alkyl-a-phenylnitrones 239, giving a mixture of the four possible isomers 240-243, but with the predominant formation of the exo-syn adduct 240 (Fig. 5.59). Diastereoselective cycloadditions proceed when mixtures of optically active 3-(2-exo-alkoxy-l-apocamphanecarbonyl)-2(3/7)-oxazolones and A-benzyl- and A-ferf-butyl-a-phenylnitrones are heated at 110 °C ... 

Konjugierte Nitro-alkene reagieren als 1,3-Dipolarophile mit aromatischen Nitril-oxiden unter Cycloaddition zu 3-Aryl-4,5-dihydro-l,2-oxazolen (10-88%)2 ... 

Numerous reactions of the betaines 86 with olefinic 1,3-dipolarophiles have been reported. lV-Methylpyridinium-3-olate (111) with electron-deficient olefins gives the adducts 112. - Alkynes give similar adducts (110) These adducts (110 and 112) are useful intermediates for tropolone synthesis. Quaternization to methiodides (113, 115) and treatment with base gives dimethylaminotropones (114) which are hydrolyzed to tropolones (116). Good syntheses of stipitatic acid (116 R = COjH, R = OH) and hinokitiol (116 R = H, R = CHMe ) have been achieved by this route (Scheme 5). Similar transformations have been achieved using the N-phenyl betaine 86 (R = Ph, R = H) which is more reactive but whose adducts are difficult to quaternize. A difference is observed when benzyne is... 

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