1.3- Dipolar cycloaddition reactions heating azide

Compound 156 (prepared by reaction of tetrabromocyclopropene and 2,5-dimethylfuran) underwent dipolar cycloaddition with phenyl azide to produce the fused triazole 157. The reaction was carried out in dichloromethane at room temperature over 2 days. This lower reaction temperature allowed for the isolation of the adduct 157, which was established by X-ray crystallographic analysis to be the product of ct>-selective addition. Heating triazole 157 in benzene at reflux for 2 h resulted in ring expansion producing a 1 1 mixture of compounds 158 and 159 (Scheme 16) <2004JOC570>. 

Unlike the mesoionic 1,2,3-oxadiazoles (see Chapter 5.03), mesoionic 1,2,3,4-oxatriazoles 5 and 6 do not undergo 1,3-dipolar cycloaddition reactions. Azides formed by loss of carbon dioxide from anhydro-5-hydroxy-l,2,3,4-oxatria-zolium hydroxides 4, on prolonged heating with lithium chloride, may be trapped by cycloaddition to an alkyne < 1996CHEC-II(4)679>. 

The copper-catalyzed 1,3-dipolar cycloaddition of organic azides and alkynes (click chemistry) has been the subject of intense research due to wide functional group tolerance, operational ease, and clean formation of the 1,2,3-triazoles. These reactions are particularly amenable to microwave heating, and a host of new compounds and materials have been created using this methodology." -" ... 

A range of indolo(triazolo)-l,4-diazepine derivatives 104 were obtained by a microwave-heated three-component reaction involving tandem N-alkylation of indole 101 with epichlorohydrin 102, ring-opening of the epoxide with azide 103, and intramolecular azide-alkyne 1,3-dipolar cycloaddition reactions (13BJO401). Fused triazolodiazepinones were obtained via azide-alkyne 1,3-dipolar cycloaddition followed by lactamization (13JHC430). 

Azides can partake in stereoselective dipolar cycloaddition reactions with olefins. The unstable resulting triazolines typically expel N2 under the conditions of the cycloaddition reaction, leading to the corresponding stable azir-idines. Cha has reported that heating of azide 32 leads directly to aziridine 33 as a single diastereomer (Scheme 18.8) [55]. The allylic stereocenter resident in 32 thus effectively controls the stereochemical outcome of the transformation. The product aziridine 33 was subsequently elaborated into 6,7-di-epi-castanospermine (34). 

Use of unsubstituted acetylene as a substrate in 1,3-dipolar cycloadditions with azides results in 4,5-unsubstituted triazoles. The reactions have to be carried out under pressure. In an example given in Equation (23) showing synthesis of an antibacterial agent, a solution of azide 1049 in dimethoxyethane is transferred to a pressure bomb that is then charged with acetylene and heated at 90 °C for 12 h to give triazole derivative 1050 in 74% yield <2003BMC35>. 

Triazoles are generally prepared by the 1,3-dipolar cycloaddition of an alkyne with an azide at elevated temperatures. Thus, reaction of organic azides with acetylenic amides was significant only after 12 h refluxing in toluene. As a contrast, microwave dielectric heating at 55-85 °C under solvent-free conditions furnished the corresponding disubstituted... 

Reaction of phenyl azide and benzyl cyanide (in EtOH in the presence of EtONa at r.t.) surprisingly does not lead to the expected product of a 1,3-dipolar cycloaddition (A), but to 5-amino-l,4-diphenyl-l,2,3-triazole (B, 80%). Triazole B isomerizes readily on heating in pyridine solution to give 5-anilino-4-phenyl-1,2,3-triazole (C). 

Another interesting type of 1,3-dipolar cycloaddition with azides involves condensation with nitriles as dipolarophiles to form tetrazoles. These products are of particular interest to the medicinal chemist, because they probably constitute the most commonly used bioisostere of the carboxyl group. Reaction times of many hours are typically required for the palladium-catalyzed cyanation of aryl bromides under the action of conventional heating. The subsequent conversion of nitriles to tetrazoles requires even longer reaction times of up to 10 days to achieve completion. Under microwave irradiation conditions, however, the nitriles are rapidly and smoothly converted to tetrazoles in high yields. An example of a one-pot reaction is shown in Scheme 11.54 [110], in which the second step, i.e. the cycloaddition, was achieved successfully under the action of careful microwave irradiation. The flash heating method is also suitable for conversion of 212 and 214 to tetrazoles 213 and 215, respectively, on a solid support, as shown in Scheme 11.54. 

An interesting intramolecular cycloaddition reaction of indoles with azides has also been reported. Heating solutions of l-(D-azidoalkylindoles 199, which bear an electron-attracting substituent (e.g., CHO, COMe, C02Me, CN) at C-3, has led to the formation of tricyclic indoles 201 as products [87] (Scheme 55). The authors suggest that after the initial 1,3-dipolar cycloaddition, the intermediate triazoline 200 loses nitrogen (perhaps via an aziridine intermediate) to produce the tricyclic products 201. 

Ciufolini and co-workers demonstrated the use of 1,3-dipolar azide-olefin cycloaddition reactions in the total synthesis of ( )-FR66979 (52) [25], an antitiunor agent which is structurally related to the mitomycins [26]. Thus, the triazoline 50 was obtained as a single diastereomer by smooth cycloaddition of the activated double bond and the dipole in 49 by heating in toluene. Brief photolysis of 50 provided aziridine 51, which fragmented to 52 (Scheme 8B). Other intramolecular azide-alkene cycloaddition in natural product synthesis is illustrated by a munber of examples [27-32]. 

A soln. of 4,4-dimethyl-2-phenylthiazole-5(4//)-thione and 1.5 eqs. benzyl azide in toluene heated at 90° with exclusion of light and moisture - N-(4,4-dimethyl-2-phenylthiazol-5(4//)-ylidene)benzylamine. Y 85%. Reaction is thought to proceed via 5-spiro-l,2,3,4-thiatriazoles, formed by 1,3-dipolar cycloaddition. F.e.s. S. Pekcan, H. Heimgartner, Helv. Chim. Acta 77, 1673-80 (1988). 

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