1,3-dipolar cycloaddition reactions cycloadduct

The Lewis acid-catalyzed 1,3-dipolar cycloaddition reaction of nitrones to a,/ -un-saturated carbonyl compound in the presence of Lewis acids has been investigated by Tanaka et al. [31]. Ab-initio calculations were performed in a model reaction of the simple nitrone 18 reacting with acrolein 1 to give the two cycloadducts 19 and 20 (Scheme 8.7). 

Dipolar cycloaddition reactions of thioisoraunchnones (l,3-thiazolium-4-olates) have not been as extensively studied as those of munchnones (l,3-oxazolium-5-olates) despite offering rapid access to novel heterocyclic compounds. The cycloaddition of the thioisomunchnone (52) with trans-P-nitrostyrene results in the formation of two diastereoisomeric 4,5-dihydrothiophenes (53) and (54) via transient cycloadducts. These cycloadducts then undergo rearrangement under the reaction conditions <96JOC3738>. 

Despite the lack of success in the attempts at intramolecular cycloaddition with substrates 83 and 91, a moderately promising outcome was observed for the nitroalkene substrate (98, Scheme 1.10c). Heating a dilute solution of oxido-pyridinium betaine 98 in toluene to 120 °C produced a 20 % conversion to a 4 1 mixture of two cycloadducts (110 and 112), in which the major cycloadduct was identified as 110. While initially very encouraging, it became apparent that the dipolar cycloaddition reaction proceeded to no greater than 20 % conversion, an outcome independent of choice of reaction solvent. Further investigation, however, revealed that the reaction had reached thermodynamic equilibrium at 20 % conversion, a fact verified by resubmission of the purified major cycloadduct 110 to the reaction conditions to reestablish the same equilibrium mixture at 20 % conversion. 

Related to the nitrile oxide cycloadditions presented in Scheme 6.206 are 1,3-dipolar cycloaddition reactions of nitrones with alkenes leading to isoxazolidines. The group of Comes-Franchini has described cycloadditions of (Z)-a-phenyl-N-methylnitrone with allylic fluorides leading to enantiopure fluorine-containing isoxazolidines, and ultimately to amino polyols (Scheme 6.207) [374]. The reactions were carried out under solvent-free conditions in the presence of 5 mol% of either scandium(III) or indium(III) triflate. In the racemic series, an optimized 74% yield of an exo/endo mixture of cycloadducts was obtained within 15 min at 100 °C. In the case of the enantiopure allyl fluoride, a similar product distribution was achieved after 25 min at 100 °C. Reduction of the isoxazolidine cycloadducts with lithium aluminum hydride provided fluorinated enantiopure polyols of pharmaceutical interest possessing four stereocenters. 

The utility of a new fluorine supported chiral auxiliary was established in a series of catalyzed and uncatalyzed 1,3-dipolar cycloaddition reactions with diphenylnitrone (637b) (Scheme 2.281) (797). The yields and selectivities of the cycloadducts (645a—d) compare favorably with those obtained with conventional Evans-type auxiliaries (798). Purification of the products was greatly improved by using fluorous solid phase extraction (FSPE). 

The 1,3-dipolar cycloaddition of nitrones to vinyl ethers is accelerated by Ti(IV) species. The efficiency of the catalyst depends on its complexation capacity. The use of Ti( PrO)2Cl2 favors the formation of trans cycloadducts, presumably, via an endo bidentate complex, in which the metal atom is simultaneously coordinated to the vinyl ether and to the cyclic nitrone or to the Z-isomer of the acyclic nitrones (800a). Highly diastereo- and enantioselective 1,3-dipolar cycloaddition reactions of nitrones with alkenes, catalyzed by chiral polybi-naphtyl Lewis acids, have been developed. Isoxazolidines with up to 99% ee were obtained. The chiral polymer ligand influences the stereoselectivity to the same extent as its monomeric version, but has the advantage of easy recovery and reuse (800b). 

This route relies on 1,3-dipolar cycloaddition reactions a series of dihydropyrrolizines 213 were synthesized by heating the proline derivatives 211 with dimethyl acetylenedicarboxylate (DMAD) at 130-140 °C in the presence of acetic anhydride. Reaction between 211 and AczO provides the mesoionic oxazalone intermediate 212 which adds to dimethyl acetylenedicarboxylate, giving a cycloadduct, which undergoes spontaneous decarboxylation leading to 213 (Scheme 50) <1998JME4744, 1977JME812>. 

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. - ... 

Apparently independently, Markl et al. (139) and Regitz and co-workers (140-142) discovered that 1,3-dipolar cycloaddition reactions of mtinchnones and phosphaalkenes or phosphaalkynes provide a direct synthesis of 1,3-azaphospholes (240) (Table 10.7). The intermediate cycloadducts cannot be isolated. The various phosphaalkynes were generated from phosphaalkenes or, in the case of methyli-dynephosphane (239, R" =H), by flash vacuum pyrolysis of either 239 (R" = f-Bu) or dichloromethylphosphine. 

The 1,3-dipolar cycloaddition reactions of several other mesoionic heterocycles have been investigated since Potts review (1). Kato et al. (113,114,123) found that the l,3-thiazohum-5-olate (358) ring system affords low yields or complex reaction mixtures with benzocyclopropene (113), benzocyclobutadiene (114), and tropone (123). Likewise, Vedejs and Wilde (209) isolated in low yields a cycloadduct of 358d with thiopivaldehyde, along with a ring-opened thiamide. Also, 1,3-thiazo-lium-5-olate 359 reacts with thiopivaldehyde to give 360 (209). 

Wilcox and co-workers (145) reported that the stereoselectivity of 1,3-dipolar cycloaddition reactions can be controlled in a predictable manner when ion pairs are located at a proper position near the reaction site (Scheme 11.40). He has employed an A-phenylmaleimide substrate having a chiral center in the substituent at ortho position of the phenyl group. Due to serious steiic hindrance, this phenyl group suffers hindered rotation around the aryl-nitrogen bond (rotation barrier 22 kcal/mol). Four diastereomeric cycloadducts are possible in the cycloaddition step with a nitrile oxide. When the cycloaddition reaction is carried out in... 

Cyclobut[c]thiophene also undergoes 1,3-dipolar cycloaddition reactions with nitrones and nitrile oxides to produce cycloadducts, such as 80, albeit in moderate yields (Scheme 9) <1999J(P1)605>. 

Substituted l,2,4-triazoline-3,5-diones are excellent dienophiles which react rapidly at room temperature with oxepins, but particularly with the arene oxide valence tautomer. A similar [4+2] cycloaddition reaction between the episulfide tautomer of thiepin (44) and 4-phenyl-l,2,4-triazoline-3,5-dione has been reported (74AG(E)736>. Benzene episulfide (the valence tautomer of thiepin 44) was generated in situ by thermal decomposition of the diepisulfide (151) at 20 °C and trapped as a cycloadduct at the same temperature (equation 34). A 1,3-dipolar cycloaddition reaction between thiepin (152) and diazomethane has been reported (56CB2608). Two possible cycloadduct products are shown since the final structure has not been unequivocally established (equation 35). 

Bora and co-workers44 have developed a microwave-assisted three-component synthesis of indolizines. The reaction involves a 1,3-dipolar cycloaddition reaction between the in situ generated dipole (from the bromoacetophenone and pyridine) and acetylene, Scheme 5.26. The developed method provides fast access to cycloadducts, which otherwise are accessible only through multi-step synthesis. 

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