Intramolecular Cycloaddition Reactions with Azides

Because intramolecular cycloaddition reactions with azides work weU by simple heating, no catalyst is reqtiired, and as a consequence, no such catalyzed reactions are described. 

Picryl azide and sulfonyl azides react with ketene AtA -acetals to give switter ionic linear adducts. The intramolecular cycloaddition reaction of azides to ketene S,S-acetals at 130 °C proceeds with loss of nitrogen to produce cyclic imines . ... 

Buchanan et al. (48) reported a new route to the synthesis of the chiral hydroxy-pyrrolidines 234 and 238 from D-erythrose (230) via an intramolecular cycloaddition of an azide with an alkene (Scheme 9.48). Wittig reaction of the acetonide 230 with (carbethoxyethylene)triphenylphosphorane gave the ( ) and (Z) alkenes 231 and 232. On conversion into the triflate followed by its reaction with KN3, the ( ) isomer 231 allowed the isolation of the triazoline 234 in 68% overall yield, which on treatment with sodium ethoxide afforded the diazo ester 235 in 86% yield. 

Cha and co-workers (54) described an enantioselective total synthesis of (—)-slaframine (269) based on an intramolecular cycloaddition of an azide (Scheme 9.54). On reaction with NaN3 in DMF at 60 °C followed by intramolecular... 

Schkeryantz and Pearson (59) reported a total synthesis of ( )-crinane (298) using an intramolecular azide-alkene cycloaddition (Scheme 9.59). The allylic acetate 294 was first subjected to an Ireland-Claisen rearrangement followed by reduction to give alcohol 295, which was then converted into the azide 296 using Mitsunobu conditions. Intramolecular cycloaddition of the azide 296 in refluxing toluene followed by extrusion of nitrogen gave the imine 297 in quantitative yield. On reduction with sodium cyanoborohydride and subsequent reaction with... 

The intramolecular 1,3-dipolar cycloaddition reaction of azides has become an increasingly useful process for the construction of natural products and molecules of theoretical interest.192 193 For example, 2-substituted azido enone (238) was prepared from the corresponding bromide by treatment with sodium azide. Thermolysis of this material afforded aziridinyl ketone (240) presumably via a transient dipolar cycloadduct (239).193 Ketone (240) was subsequently converted to an intermediate previously used to prepare histrionicotoxin (241 Scheme 56). 

The nitrene 28 is not produced from the azide precursor, but from heterocycles via photolysis and thermolysis as shown in Sch. 11 [20]. Iminoacyl nitrenes react intramolecularly giving benzimidazoles with good yields (Sch. 11), and, dependending on the precursor used and the reaction conditions, varying amounts of carbodiimides are obtained. The reactivity of the acyl nitrenes is influenced by the substituent connected to the acyl group (see Sch. 10), however all acyl nitrenes are quite reactive and therefore rather unselective. Apart from cycloaddition reactions with Tt-bonds, insertion reactions into a-bonds, additions to lone pair electrons of... 

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. 

Using rw-chloroalkenes (e.g., 42) in 1,3-dipolar cycloaddition reactions, Pearson et al. described the synthesis of several alkaloids [20-22]. The reaction proceeds by an intramolecular cycloaddition of an azide onto an alkene, producing an intermediate triazohne. Fragmentation of the triazoUne and rearrangement to a monocyclic imine occurs, which is internally N-alkylated by the alkyl chloride, resulting in iminium ion 43. Reduction with sodium borohydride leads to the racemic lycorane (44). 

A homogeneous Ag(I)-catalyst (65) has been developed for the 3 -I- 2-cycloaddition reaction of azides to terminal alkynes to form the corresponding 1,4-triazoles. A simple metal-free synthesis of pentafluoroalkylated 1,2,3-triazoles has been developed from the 1,3-dipolar cycloaddition reaction of azides with methyl 2-perfluoroalkynoates. Again, the intramolecular alkyne-azide Huisgen 3 -I- 2-cycloaddition reaction in water is an example of Click reaction in the absence of a metal catalyst. The Cu(I)-catalysed azide-alkyne 3-1-2-cycloaddition reaction yielded 1,4-disubstimted 1,2,3-triazoles in excellent yields in 2-25 min under solvent-free conditions. The use of 16-electron... 

The direct, stereoselective conversion of alkynes to A-sulfonylazetidin-2-imines 16 by the initial reaction of copper(l) acetylides with sulfonyl azides, followed, in situ, by the formal [2+2] cycloaddition of a postulated A-sulfonylketenimine intermediate with a range of imines has been described <06AG(E)3157>. The synthesis of A-alkylated 2-substituted azetidin-3-ones 17 based on a tandem nucleophilic substitution followed by intramolecular Michael reaction of primary amines with alkyl 5-bromo-4-oxopent-2-enoates has been... 

Another theoretical investigation deals with the intramolecular [3+2] dipolar cycloaddition (Huisgen reaction) of azides and nitriles (Scheme 2) to form tetrazoles <2003JOC9076>. 

Vogel and Delavier (26) reported a synthesis of the 6-azabicyclo[3.2.2]nonane skeleton 130 using an intramolecular azide-alkene cycloaddition strategy (Scheme 9.26). When refluxed in xylene, the azide 126 underwent an intramolecular 1,3-dipolar cycloaddition with the internal alkene. Nitrogen extrusion and subsequent rearrangement led to a mixmre of compounds 128, 129, and 130. Reactions of azides with the double bond of dienes were also used in various total syntheses of alkaloids, and will be discussed later in Section 9.2.2. 

Isopropylidene-D-erythrose (104) was treated with Wittig reagent to give the olefin 110. This was subjected to a Mitsunobu reaction to afford the azide intermediate 111, whose intramolecular cycloaddition in refluxing benzene produced the bicyclic iminium ion 112. Treatment of 112 with tm-butylamine gave 113, which upon hydroboration using the modification of Schultz method " afforded the acetonides 48 as a major product in addition to 114 (7%). Aqueous acid hydrolysis of 48 afforded 1 in 39% overall yield from 104. 

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