Azide-alkene cycloadducts

Azides are very versatile and valuable synthetic intermediates, known for their wide variety of applications, and have been employed for the synthesis of a number of important heterocyclic compounds. Azides also represent a prominent class of 1,3-dipoles, and their cycloaddition to multiple tt-bonds is an old and widely used reaction (1988CR297). The dipolar cycloaddition of an azide to an alkene furnishes a triazoline derivative (2003MI623). Azide-alkene cycloadducts can extrude nitrogen at elevated temperatures to form aziridines or imines, depending upon the substrate and reaction conditions. The cycloaddition of azides with alkynes affords triazolidine derivatives which have been a focus in the area of chemical biology and have received much recent attention (2008AGE2596, 2008CR2952). In this section of our review, we recount some developments of the 1,3-dipolar cycloaddition reaction of azides that have been used for the synthesis of various alkaloids. 

Conformational constraints induced by various ortho-substitutents in 1-aUyloxy-2-azidomethylbenzenes (97) were used to accelerate intramolecular cycloadditions of the azide group to alkenes (21) (Scheme 9.21). For the unsubstituted azide 96, high temperature was required for the cycloaddition and the yield of the cycloadduct 100 was low. The monosubstituted azide 97 underwent cycloaddition in refluxing benzene in 10 h to give the cycloadduct 101 in good yield. Disubstituted azides 98 and 99 underwent 1,3-dipolar cycloaddition in 5-7 h to give the triazolines 102 and 103. 

These iminosilanes react with H-acid compounds like water and ethanol by insertion into the O-H bond, with acetone and 2,3-dimethyl-1,3-butadiene to give alkenes, and with methacrolein, ethylvinylether, silyl and aryl azides to give cycloadducts. 

The dipolar cycloaddition of an alkyl azide with an alkene to form an aziridine has been exploited in the total synthesis of the alkaloid ( )-aspidospermidine <20050BC213>. Enone 353 was prepared in 11 steps from 3-ethoxycyclohexenone and coupled to 2-iodo nitrobenzene under Ullman cross-coupling conditions. The acetate group of 354 was hydrolyzed and the resulting alcohol converted to an azide using standard conditions in 75% overall yield. The cycloaddition of the azide with the enone was conducted in refluxing benzene for 3 days. The fused-ring aziridine 355 was the only product isolated. None of the initial dipolar cycloadduct triazoline was observed. The... 

Many of the cycloadducts formed from the dipoles in Table 15.3 are unstable, leading to other products. The reaction of alkyl azides with alkenes generates triazolines (15-54), which extrude nitrogen (N=N) upon heating or photolysis to give an aziridine. 

An unusual influence of water on the rate of 1,3-dipolar cydoadditions was first observed when 2,6-dichlorobenzonitrile N-oxide was allowed to react with 2,5-di-methyl-p-benzoquinone [50]. Likewise, bromonitrile oxide, generated in water at acidic pH, gave cycloadducts effidendy with water-soluble alkenes and alkynes [51]. In highly aqueous media remarkable accelerations for the cycloaddition of phenyl azide to norbomene were observed [52]. 

Some 1,3-dipoles, such as azides and diazoalkanes, are relatively stable, isolable compounds however, most are prepared in situ in the presence of the dipolarophile. Cycloaddition is thought to occur by a concerted process, because the stereochemistry E or Z) of the alkene dipolarophile is maintained trans or cis) in the cycloadduct (a stereospecihc aspect). Unlike many other pericycUc reactions, the regio- and stereoselectivities of 1,3-dipolar cycloaddition reactions, although often very good, can vary considerably both steric and electronic factors influence the selectivity and it is difficult to make predictions using frontier orbital theory. 

Shea et al. investigated whether strain involved in alkenes affects reactivity and regiochemistry of the intermolecular 1,3-dipolar cycloaddition reaction [14]. Therefore, the addition of picryl azide (18) with a series of mono-and bicyclic olefins including frans-cycloalkenes and bridgehead alkenes was studied (Scheme 5). In the cases of czs-cyclooctene (16) and ci5-cyclononene (17), decomposition of the initially formed cycloadducts 19 and 20 followed... 

Another apparent example of the trapping of a vinylnitrene has been reported by Nomura and coworkers.These workers found that the thermolysis of vinylazides in the presence of electron-deficient alkenes resulted in the formation of iV-vinylaziridines 277 and 2l -pyrrolines 278. Although this reaction was interpreted in terms of the trapping of a vinylnitrene intermediate (path a), it seems that concerted 1,3-dipolar cycloaddition of the azide followed by extrusion of nitrogen from a transient cycloadduct 279 could also rationalize the results (path b). 

The [3-1-2] cycloaddition reaction of azides with alkenes affords 1,2,3-triazolines. Even electron-poor oleflns react with butyl- and phenyl azide to give 1,2,3-triazolines. Better yields are obtained when the reaction of these oleflns is conducted under high pressure (12 Kbar, room temperature, 24 h). In this manner, the cycloadducts 52 and 53 are obtained in... 

Photoclick chemistry based on tetrazole derivatives was investigated from synthetic and biological viewpoints in recent years. [3 + 2] Cycloadducts were obtained by irradiation of tetrazoles (55) and (56) with alkenes and allynes. The denitrogenation of vinyl azides (57) to 2H-azirines (58) by using photoflow reactor produced nitrile ylides, giving [3 + 2] cycloadducts (60) with acrylonitrile (59) as 1,3-dipolarophiles (Scheme 18). ... 

Since vinyl azides like 34 are electron-rich olefins, [2 + 2] cycloaddition with electron-deficient alkenes such as diphenylketene could lead to azidocyclobutanes. " The stability of the cycloadducts 211, prepared from 34 or 52 and tetracyanoethene (TCNE), allowed characterization in solution but not isolation of these products because rapid ring-expansion regioselectively afforded the dihydropyrroles 212 already at room temperature (Scheme 5.25). "" A similar mechanism via [2 + 2] cycloaddition and quick ring-enlargement may perhaps explain the formation of 213 from 52 and 4-phenyl-l,2,4-triazole-3,5-dione (PTAD). In this " " and other " " cases, however, different interpretations were offered. The 2-azidobuta-l,3-dienes 92a,b underwent [4 + 2] cycloaddition in the... 

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