1.3- dipolar cycloaddition thermal

Thermal reactions and 1,3-dipolar cycloaddition reactions Thermally mesoionic oxatriazoles are relatively stable. Heating of (85) in tolane (97) at 200 °C for 20 d in the presence of LiCl induces C02 fragmentation and formation of cycloadduct (99) in 37% yield. There is no bimolecular reaction as found in the case of the sydnones and isosydnones (equation 56) (68CB536). 

Dipolar Cycloadditions. The asymmetric induction for a 1,3-dipolar cycloaddition of phenylmenthyl acrylate is not as good as in the [4 + 2] cycloadditions. The thermal decomposition of di-azofluorene in the presence of the acrylate produces the spirocy-clopropane in 96% yield, but with only a 20% de (eq 4). ... 

Clusiacyclol A 171 and B 172 were isolated from the fruit extract of Clusia multiflora in 1994 by Monache and coworkers [90]. The compounds with oxacyclobutaindan core units have been synthesized previously by using intramolecular [2-1-2] photochemical [73,77,91] or acid-catalyzed cationic [75] cycloaddition reactions of various suitably substituted benzopyrans. Argade and coworkers have demonstrated a simple and efficient phenol-directed intramolecular diastereoselective dipolar thermal/base-catalyzed [2-1-2] cycloaddition approach to novel biologically important natural and synthetic benzopyran systems (Scheme 12.41) [92]. The trihydroxybenzophenone 167 was synthesized with high yield from trimethoxybenzene 166 via... 

The dipolar cycloaddition of 2-diazopropane to l-methyl-3-phenylpyridazin-6(l//)-one takes place through an unstable adduct which thermally decomposes to a 1,2-diazepinone, a pyridazinone and diazanorcaradiene derivative (Scheme 46). 

A variety of 1-azirines are available (40-90%) from the thermally induced extrusion (>100 °C) of triphenylphosphine oxide from oxazaphospholines (388) (or their acyclic betaine equivalents), which are accessible through 1,3-dipolar cycloaddition of nitrile oxides (389) to alkylidenephosphoranes (390) (66AG(E)1039). Frequently, the isomeric ketenimines (391) are isolated as by-products. The presence of electron withdrawing functionality in either or both of the addition components can influence the course of the reaction. For example, addition of benzonitrile oxide to the phosphorane ester (390 = C02Et) at... 

Fluorinated cyclobutanes and cyclobutenes are relatively easy to prepare because of the propensity of many gem-difluoroolefins to thermally cyclodimerize and cycloadd to alkenes and alkynes. Even with dienes, fluoroolefins commonly prefer to form cyclobutane rather than six-membered-ring Diels-Alder adducts. Tetrafluoroethylene, chlorotrifluoroethylene, and l,l-dichloro-2,2-difluoroethyl-ene are especially reactive in this context. Most evidence favors a stepwise diradical or, less often, a dipolar mechanism for [2+2] cycloadditions of fluoroalkenes [S5, (5], although arguments for a symmetry-allowed, concerted [2j-t-2J process persist [87], The scope, characteristic features, and mechanistic studies of fluoroolefin... 

Four-membered heterocycles are easily formed via [2-I-2] cycloaddition reac tions [65] These cycloaddmon reactions normally represent multistep processes with dipolar or biradical intermediates The fact that heterocumulenes, like isocyanates, react with electron-deficient C=X systems is well-known [116] Via this route, (1 lactones are formed on addition of ketene derivatives to hexafluoroacetone [117, 118] The presence of a trifluoromethyl group adjacent to the C=N bond in quinoxalines, 1,4-benzoxazin-2-ones, l,2,4-triazm-5-ones, and l,2,4-tnazin-3,5-diones accelerates [2-I-2] photocycloaddition processes with ketenes and allenes [106] to yield the corresponding azetidine derivatives Starting from olefins, fluonnaied oxetanes are formed thermally and photochemically [119, 120] The reaction of 5//-l,2-azaphospholes with fluonnated ketones leads to [2-i-2j cycloadducts [121] (equation 27)... 

Diethylamino-4-(4-methoxyphenyl)-isothiazole 5,5-dioxide 6 is (95T(51)2455) a highly reactive partner in 1,3-dipolar cycloadditions with several dipoles. Azomethine yhdes, such as oxazolones 7 and miinchnones 8, afforded with 6 bicychc pyrrolo[3,4-d]isothiazole 5,5-dioxides 9, 10, 11 in satisfactory yield. The regioselectivity of the reaction was excellent. The thermal behavior of these new bicychc systems was investigated. When heated at their melting point or shghtly above, triarylpyrroles 12, 13 were obtained through SOj and AtiV-diethylcyanamide ehmination. 

The phenylhydrazones of 2-[(2-alkenyl)amino]-3-formyl-4//-pyrido-[1,2-n]pyrimidin-4-ones 242 underwent a thermally induced intramolecular 1,3-dipolar cycloaddition leading to a mixture of tetracyclic compounds 243 and 244 at room temperature or to 244 under reflux (96T901). Derivatives 243 were not stable and converted to compounds 244 gradually on standing or on heating their ethanolic solutions in air. The ( )-hydrazones 245 could be isolated only in the case of... 

A mechanism for this reaction has been proposed [75], The first key intermediate in the reaction is the copper(I) acetylide 42. The additional ligand may be solvent or H2O. The acetylene moiety in 42 is activated for a 1,3-dipolar cycloaddition with the nitrone to give intermediate 43, with introduction of chirality in the product. A possible route to ris/traws-41 might be via intermediate 44. Finally, the cis isomer is isomerized into the thermally more stable trans-41. It should be mentioned that the mechanism outlined in Scheme 6.32 was originally proposed for a racemic version of the reaction to which water was added. 

Dipolar [3 + 2] cycloadditions are one of the most important reactions for the formation of five-membered rings [68]. The 1,3-dipolar cycloaddition reaction is frequently utihzed to obtain highly substituted pyrroHdines starting from imines and alkenes. Imines 98, obtained from a-amino esters and nitroalkenes 99, are mixed together in an open vessel microwave reactor to undergo 1,3-dipolar cycloaddition to produce highly substituted nitroprolines esters 101 (Scheme 35) [69]. Imines derived from a-aminoesters are thermally isomerized by microwave irradiation to azomethine yhdes 100,... 

Chapter 6 looks at concerted pericyclic reactions, including the Diels-Alder reaction, 1,3-dipolar cycloaddition, [3,3]- and [2,3]-sigmatropic rearrangements, and thermal elimination reactions. The carbon-carbon bond-forming reactions are emphasized and the stereoselectivity of the reactions is discussed in detail. 

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

The nonsymmetrical quinolizidine 373 was obtained from the acyclic symmetrical precursor 372 by means of a reaction sequence comprising azide formation, intramolecular 1,3-dipolar cycloaddition, thermal triazoline fragmentation to a diazoalkane, and Michael addition individual steps, as shown in Scheme 85 <2005CC4661>. 

Treatment of benzo[c][l,5]naphthyridine with dichlorocarbene, formed from the thermal decomposition of sodium trichloroacetate, gives the corresponding iV-dichloromethylide, 1,3-dipolar cycloaddition of which with DMAD, with loss of HC1, gives the corresponding pyrrolonaphthyridine 284 (Equation 98) <1995M227>. In the [1,6]- and [1,7]-naphthyridine series, compounds 285 and 286 are obtained by the same route and in the [l,8]naphthyridine series compound 287 is obtained from the parent naphthyridine, dichlorocarbene, and dimethyl maleate followed by oxidation (Equation 99) <1998RJ0712>. 

A second category of silene reactions involves interactions with tt-bonded reagents which may include homonuclear species such as 1,3-dienes, alkynes, alkenes, and azo compounds as well as heteronuclear reagents such as carbonyl compounds, imines, and nitriles. Four modes of reaction have been observed nominal [2 + 2] cycloaddition (thermally forbidden on the basis of orbital symmetry considerations), [2 + 4] cycloadditions accompanied in some cases by the products of apparent ene reactions (both thermally allowed), and some cases of (allowed) 1,3-dipolar cycloadditions. 

Pyrazoles can be synthesized by thermal cycloreversion of adducts formed in the 1,3-dipolar cycloaddition of alkyldiazoacetates with norbornadiene. The rate of the primary process of cycloaddition is accelerated by iron pentacarbonyl (Scheme 88)155 a similar catalytic effect has been observed during the formation of ethyl 5-phenyl-A2-pyrazoline-3-carboxylate from cycloaddition of ethyl diazoacetate and styrene.155 Reactions of this type are catalyzed presumably because of coordination of one or both reactants to the transition metal, and a wider study of the effect of a variety of complexes on 1,3-dipolar cycloaddition processes would be valuable. 

The 1,3-dipolar cycloaddition of azides to alkynes is a versatile route to 1,2,3-tri-azoles. Different combinations of substituents on the azide and on the alkyne allow the preparation of diverse N-substitutcd 1,2,3-triazoles. Katritzky and Singh have described the synthesis of C-carbamoyl-1,2,3-triazoles by microwave-induced cydoaddition of benzyl azides to acetylenic amides (Scheme 6.220) [393]. Employing equimolar mixtures of the azide and alkyne under solvent-free conditions, the authors were able to achieve good to excellent isolated product yields by microwave heating at 55-85 °C for 30 min. In general, the triazole products were obtained as mixtures of regioisomers. Control experiments carried out under thermal (oil bath)... 

A general method for the functionalization of C60 (4) is the 1,3-dipolar cycloaddition of azomethine ylides. This process was first described by Prato [94] and leads to fulleropyrrolidines. Several fulleropyrrolidines (143a-c) have been prepared under microwave irradiation by Langa et al. [72]. These authors observed that microwave irradiation again competes favorably with thermal heating and, in this way, 143 a was... 

Triazole derivatives are very interesting compounds that can be prepared by 1,3-dipolar cycloadditions between azides and alkynes. Loupy and Palacios reported that electron-deficient acetylenes react with azidoethylphosphonate 209 to form the regioisomeric substituted 1,2,3-triazoles 210 and 211 under microwaves in solvent-free conditions (Scheme 9.65) [114]. This procedure avoids the harsh reaction conditions associated with thermal cycloadditions (toluene under reflux) and the very long reaction times. 

Compounds of this type are the most common products obtained from thermal 1,3-dipolar cycloaddition of disub-stituted alkynes to azides. Many examples of such reactions can be found in Section 5.01.9. 

Benzonitrile oxide and mesitonitrile oxide undergo 1,3-dipolar cycloaddition reactions with 1,3,5-triphosphinines under mild conditions to afford fused heterocyclic compounds (Scheme 1.33), for example, 192 and 193. Oxaphosphazoles and oxadiphospholes have become accessible by thermal fragmentation reactions of such fused heterocyclic compounds (358). 

Arylsydnone-4-carbonitrile oxides, which are generated in situ by thermal dehydrochlorination of the corresponding hydroximic acid chlorides, undergo 1,3-dipolar cycloadditions with sydnone-4-carbonitriles to give 3-aryl-4-[5-(3-arylsydnonyl)-l,2,4-oxadiazol-3- yl]sydnones 228 (392). 

Diastereoselective intramolecular 1,3-dipolar cycloadditions of alkylidene-cyclopropyl nitrones provide spirocyclopropylisoxazolidines. These compounds have been shown to undergo either thermally induced ring expansion to octahydro[l]pyrindin-4-ones or to acid induced ring contraction into fS-lactams with concomitant loss of ethylene (Scheme 2.218) (710-716). Use of chiral auxiliaries, that is (L)-2-acetoxylactate can lead to enantiomerically enriched heterocycles (715). 

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