Triazolines, thermolysis

By carefully controlling the temperature and duration of reaction so as to avoid triazoline thermolysis, satisfactory yields can be achieved. A generally satisfactory procedure is to treat the azide with excess olefin at 40-70°C and terminate the reaction after 20% nitrogen evolution from the triazoline decomposition is observed.40 Increased yields are obtained at lower temperatures, although prohibitively long reaction times are required (Scheme 26)40... 

By contrast, phenyl azide and tetramethoxyethylene yield only the products of the triazoline thermolysis.274,275... 

The diazoacetonitrile-imine reaction may be considered complimentary to azide addition to cinnamonitriles because in the latter case only triazoline thermolysis products result.284 The reversed order of reactivity of the diazoacetonitrile to that of diazomethane implies an electrophilic attack on the imine and is explained in terms of a LUMOdi MC lonit[ile-HOMOin,int controlled interaction. Thus electron-rich enamines, which do not react with diazoalkanes, may be expected to react with electron-poor diazo compounds. 

Triazoline thermolysis leads to aziridines, diazo compounds, imines, or enamines a diazonium betaine is postulated as the intermediate that can undergo stabilization by different pathways,16,30,806,112,465 as depicted in Scheme 161. Imine and enamine formation may occur directly from the diazonium betaine806,112,226 237 247 or via the diazo compound.32 Acceleration of the rate of thermolysis of 4,5-dialkyl-substituted triazolines in polar solvents is commensurate with the betaine intermediate,100,112,457,466 and attempts to prove a 1,3-zwitterionic intermediate have failed 467-469... 

When electron-withdrawing groups are present on the 4-carbon, triazoline thermolysis is insensitive to solvent polarity a homolytic decomposition to a singlet diradical similar to that formed in photolysis is proposed to account for the selective formation of aziridine in these cases (Scheme 162).67,172,454 The lower thermolysis temperatures of N-aryltriazolines ( 25°C)6 7,322 as compared to those for the N-alkyl compounds ( 90° C)6 7 are consistent with the stabilization of the diradical by aryl groups. 

Several factors influence product formation in triazoline thermolysis. The stereochemistry of the triazoline adducts from cis- and trans-cyclooctene has been found to play a role in aziridine or imine formation aziridines predominate in the trans and imines in the cis isomers.86 However, the relative product ratios depend on the reaction temperature, and thermolysis of the cis-triazoline at 310°C leads to 78% aziridine as against 5% at 80°C.87... 

The overall pathway for the conversion of the unsaturated azido ether 281 to 2,5-dihydrooxazoles 282 involves first formation of the dipolar cycloaddition product 287, which thermolyzes to oxazoline 282 or is converted by silica gel to oxazolinoaziridine 288. While thermolysis or acid-catalyzed decomposition of triazolines to a mixture of imine and aziridine is well-documented [71,73], this chemoselective decomposition, depending on whether thermolysis or exposure to silica gel is used, is unprecedented. It is postulated that acidic surface sites on silica catalyze the triazoline decomposition via an intermediate resembling 289, which prefers to close to an aziridine 288. On the other hand, thermolysis of 287 may proceed via 290 (or the corresponding diradical) in which hydrogen migration is favored over ring closure. 

Scheme 33 illustrates the difference in reactivity between triazolines obtained from cyclohexanone and cyclo-pentanone enamines. Thus, the reactions of azidophosphonates 239 with cyclohexanone enamines produce unstable aminotriazolines 240 that cannot be isolated due to their spontaneous elimination of amines to provide triazoles 241. Contrary to that, triazolines 242, derived from cyclopentanone enamines, are isolated in good yield (76-88%) and cannot be converted to the corresponding triazoles even by thermolysis <1995H(40)543>. Probably, introduction of a double bond between two five-membered rings would involve too much molecular strain. 

Dipolar cycloaddition occurred preferentially at the electron-rich double bond of 22 to give the unstable triazoline 23, which on thermolysis led to extrusion of nitrogen and rearrangement to give the cyclopentenoid compound 25. The 1,3-dipolar cycloaddition-rearrangement sequence was subsequently extended to ultrasonic conditions. 

Bellavia-Lund and Wudl (43) investigated the 1,3-dipolar cycloaddition of 2-(methoxyethoxy)methyl azide with [70]fuUerene (199) (Scheme 9.43). Three isomeric triazohnes 200-202 were obtained. Thermolysis of these triazolines gave the corresponding azafiilleroids and fulleroaziridines, as a mixture, respectively. 

Sha et al. (45) reported an intramolecular cycloaddition of an alkyl azide with an enone in an approach to a cephalotaxine analogue (Scheme 9.45). Treatment of the bromide 205 with NaN3 in refluxing methanol enabled the isolation of compounds 213 and 214 in 24 and 63% yields, respectively. The azide intermediate 206 underwent 1,3-dipolar cycloaddition to produce the unstable triazoline 207. On thermolysis of 207 coupled with rearrangement and extrusion of nitrogen, compounds 213 and 214 were formed. The lactam 214 was subsequently converted to the tert-butoxycarbonyl (t-Boc)-protected sprrocyclic amine 215. The exocyclic double bond in compound 215 was cleaved by ozonolysis to give the spirocyclic ketone 216, which was used for the synthesis of the cephalotaxine analogue 217. 

Two enantioselective syntheses of (+)-biotin (293) from L-cysteine were reported based upon the intramolecular 1,3-dipolar cycloadditions of carbamoyl azides 289 and 291 by Deroose and De Clercq (58) (Scheme 9.58). Thermolysis of the carbamoyl azides 289 and 291 gave the triazolines 290 and 292, respectively. Both 290 and 292 were converted into (+)-biotin (293) in several steps. 

An efficient stereoselective synthesis of the (pyrrolidin-2-ylidene)glycinate intermediate 325 was reported in a total synthesis of carzinophilin (326), employing an intramolecular cycloaddition of an azide with an alkene (63) (Scheme 9.63). The arabinose derivative 319 was converted into the required azide 321 via the triflate 320. Thermolysis of the azide 321 at 50 °C in THF produced the unstable triazoline 322, which on rearrangement gave the (pyrrolidin-2-ylidene)glycinate 325 in 60-72% overall yield from the triflate 320. 

By using the same method, an attempt toward the synthesis of 3-epiaustraline (371) was unsuccessful (70) (Scheme 9.70). Thermolysis of the azido-diene 367 afforded the dehydropyrrolizidine 368 and the triazoline 369 in equal amounts. All attempts to hydrolyze the vinyl sulfide unit of 368 to the ketone 370 were futile, although a more conventional route to these alkaloids proved to be successful. 

Aziridines can be prepared directly from double-bond compounds by photolysis or thermolysis of a mixture of the substrate and an azide.812 The reaction has been carried out with R = aryl, cyano, EtOOC, and RS02, as well as other groups. The reaction can take place by at least two pathways. In one, the azide is converted to a nitrene, which adds to the double bond in a manner analogous to that of carbene addition (5-50). In the other pathway a 1,3 dipolar addition (5-46) takes place to give a triazoline (which can be isolated), followed by extrusion of nitrogen (7-46). Evidence for the nitrene pathway is most compelling for... 

The loss of CO, S, SO, S02 and N2 by thermolysis or photolysis has been used to make three- and four-membered rings for example, thiiranes (67) are obtained from (66) (CHEC 5.06.4.4). A2-1,2,3-Triazolines give aziridines and Wolff rearrangement of (68) gives (69). 

Huisgen, Szeimies, and Mobius have studied the addition reactions of aryl azides to a,/S-unsaturated esters and nitriles.1 4 Methyl acrylate (73) reacts with aryl azides to form l-aryl-4-carbomethoxy-A -triazolines in agreement with the orientation rule based on electronic effects. These A -triazolines are completely converted by base catalysis into the ring-opened isomer. Thus l-phenyl-4-carbomethoxy-A2-triazo ine (74) gives, in the presence of triethylamine at room temperature, methyl 3-aniline-2-diazopropionate (75). The A2-triazolines as well as the a-diazoesters are thermolabile. 74 is converted into l-phenyl-2-carbomethoxyaziridine (76) and 75 gives methyl 3-anilinoacrylate (77) as thermolysis product.262... 

Photolysis and thermolysis of 4-aryl-l,2,4-triazoline-3,5-diones (70, R = aryl) have been studied by Wamhoff and Wald (77CB1699). Photolysis produces the same products as were found in FVP. The thermal conversion of 70, R = Ph, into the corresponding s-triazolo[l,2-a]-s-triazole derivative, which takes place below the decomposition temperature of the educt, is assumed to proceed via a radical chain reaction (Scheme 8). 

Azides undergo intramolecular cycloaddition to C—C double bonds present in rings to provide a variety of novel products. Schultz et al for example, reported thermolysis of azide (206) at 110 C to afford an isolable triazoline as a single diastereomer (Scheme 64).115 A related reaction, however, gave an isomer mixture. Photochemical nitrogen extrusion from the triazoline provided a dihydropyrrole in 97% yield. 

The strained double bonds in Dewar benzene and thiophene make them good dipolarophiles in 1,3-cycloadditions. The hexamethyl,148 1,3,5-trimethyl, and perfluoro-1,3-dimethyl122 Dewar benzenes all yield a monoadduct by reaction with phenyl azide. The hexafluoro derivative, however, gives, depending on the conditions, either a monoadduct (19) or a mixture of mono-and bisadducts accompanied by an aziridine resulting from thermolysis of the triazoline ring system (Scheme 19).146... 

Orientation of addition is in accordance with general mechanistic considerations for 1,3-dipolar cycloadditions, and is highly regioselec-tive.27,34,40,171-174 The addition of p-nitrophenyl azide to styrene, however, is an exception the triazoline (21) and an aziridine obtained from thermolysis of the isomeric triazoline (20) are the products (Scheme 27).110,175... 

Based on results presented in Scheme 37, Logothetis suggested that the thermal decomposition products from the olefinic azides in the scheme are derived from triazoline intermediates formed by an intramolecular cycloaddition reaction and not by fragmentation of the azido group to a nitrene.100 However, allyl azide and 4-azido-l-pentene do not undergo internal cycloaddition because of the strain in the corresponding triazoline they fail to give aziridines and imines upon thermolysis.100... 

The results have been corroborated by further studies of o-(allyloxy)phenyl azide and 14 derivatives substituted on the allyl group. The allyloxy azide in Scheme 39 underwent complete conversion to triazoline at 35°C in 3 weeks as indicated by NMR.197 Thermolysis of o-allylphenyl azides, on the other hand, required high temperatures of the order of 155-200°C, apparently suggesting nitrene insertion reactions.197 The higher rate of decomposition of ortho-substituted phenyl azides as compared to the corresponding meta or para isomers, noted primarily in those systems where the ortho substituents have... 

Vinyl azide intramolecular cycloaddition is further illustrated by the formation of azidotriazoline 32 as a minor product in the thermolysis of the bisvinyl azide 31 (Scheme 41).200 An analogy is provided by the formation of 2,5-diphenylpyrrole from the slow decomposition of a-azidostyrene.202 Pyrrole formation is interpreted in terms of cycloaddition of the azide onto the electron-rich double bond of a second molecule to give a triazoline that loses nitrogen and rearranges to a pyrroline followed by hydrogen azide elimination (Section IV,D).203... 

Both i,2-241 242 and 1,4-dihydropyridines243 behave as enamines rather than as dienes244 in cycloaddition reactions with azides bearing electron-withdrawing groups, they provide a route for the preparation of bicycloazir-idines in quantitative yields via thermolysis of the intermediate triazolines (Scheme 60).241-242 The reactions of dienamines have been reviewed.245... 

Azide addition also occurs with the electron-poor olefinic double bond in androstene a mixture of the triazoline adduct and aziridine is obtained, the latter arising from the thermolysis of the triazoline formed by azide addition in the opposite direction (Scheme 74).251... 

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