Triazolines aziridine synthesis

The photolytic and thermolytic decomposition of azides in the presence of olefins has been applied to aziridine synthesis. However, only a limited number of steroid aziridines have been prepared in this manner. The patent literature reports the use of cyanogen azide at ca. 50° for 24 hours in ethyl acetate for the preparation of an A-nor- and a B-norsteroidal aziridine. The addition is believed to proceed via a triazoline. The reaction of cholest-2-ene with ethyl azidoformate takes place in a nonselective manner to produce a mixture of substances, including C—H insertion products. 

Dipolar cycloaddition of azides with olefins provides a convenient access to triazolines, cyclic imines, and aziridines and hence is a valuable technique in heterocyclic synthesis. For instance, tricyclic -lactams 273 - 276 have been synthesized using the intramolecular azide-olefin cycloaddition (lAOC) methodology (Scheme 30) [71]. 

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

Irradiation of triazolines with UV light of k > 240 nm, the region of maximum absorption, constitutes one of the principal methods for the synthesis of various substituted aziridines.79 "3 The photolysis reaction is essentially independent of substituent and solvent effects in some cases aziridines are accompanied by imines.79... 

Numerous aziridines have been prepared by triazoline photolysis it is the principal route to the synthesis of N-arylaziridines. Photolysis of triazolines derived from simple79,113,144 and cyclic79,87,113 olefins as well as norbomene... 

The thermolysis of triazoline adducts from other polycyclic bridgehead olefins is analogous to that of the norbornene-azide adducts (Scheme 164) and affords a route for the synthesis of various aziridine ring sys-... 

Of the numerous other aziridine syntheses, there are several multistep procedures from alkenes. Though not strictly within the scope of this review, the practising chemist will wish to consider their merits alongside the rect syntheses, and the main possibilities are summarized in Scheme 8. There are several good recent reviews, - and two older compilations remain very useful. - Syntheses of those intermediates of Scheme 8 accessible from alkenes are described in later sections of tiie present review, and syntheses of epoxides (Volume 6, Chapter 1.1 and Volume 7, Chapters 3.1 and 3.2) and triazolines (Volume 5, Ch ter 3.1) are described elsewhere in Comprehensive Organic Synthesis . It is important to note that by careful choice of route one can either commence with alkene (14) and retain the cisitrans stereochemistry in the resulting aziridine (16), or start with alkene (13) and change the cisitrans relatitm-ships of the substituents. 

The intramolecular azide cycloaddition has also been used in approaches to the aspidosperma alkaloids <2004TL919, 20050BC213>. The cycloaddition of 123 proceeds directly to aziridine 124 in 80% yield (Equation 28) <2004TL919>. This is an interesting transformation in that none of the initially formed triazoline is observed and because of the high regioselectivity of the addition. A conceptually related approach to the synthesis of cephalotaxine has also been reported <1997TL4347>. 

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... 

Intramolecular 1,3-dipolar cycloaddition of azide (81) proceeds through a triazoline and vinyl-aziridine (82) and results in the formation of tetrahydropyrrolizidine (83) and (84). This represents a formal total synthesis of supinidine. Thermolysis of vinyl aziridine (82) leads to pyrrolizidine (84) probably via azomethine ylides, while the nucleophilic opening leads exclusively to (83) through an intermediate allylic iodide (85). The latter is produced as a mixture of (E) and (Z) isomers but is converted to (83) via an equilibrium and recyclization of the (Z)-isomer (Scheme 30) <85TL3523, 85TL3527). 

Synthesis of triazolines or aziridines from azides by photodecomposition or flash vacuum pyrolysis of 1,2,3-triazolines. 

Photoelimination of nitrogen from triazolines can similarly be employed in the synthesis of aziridines. Thus, the triazolines (41) have been converted in this way... 

The synthesis of monosubstituted A -l,2,3-triazolines from 1-arylazo-aziridines (11.1-5) has been reported to give excellent yields (Eq. 9). The starting materials (11.1-5) are often unstable and were isomerized without purification. A more recent report provides a promising alternative and extension for the synthesis of these compounds from dimethyloxosulfonium methylide (11.1-7) (Eq, 10). The use of 4-nitrophenyl- or benzoyl azide produced only triazenes. ... 

The reaction is an important synthetic route to triazolines and their derivatives [5-7] such as cycUc imines or aziridines and is hence a valuable technique in the synthesis of heterocycles [8]. The reaction rate is dependent on the dipolarophile. Whereas strained olefins, such as norbornene, react readily, terminal alkenes react extremely slowly [9]. 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

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]. 

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. 

In a related example, Sha and coworkers reported on the intramolecular cycloaddition of azido-enone 95 as the key step for a total synthesis of ( )-desamylperhydrohistrionicotoxin 98 (Scheme 23) (1991JOC2694). The reaction sequence proceeds by an initial dipolar cycloaddition of azide 95 to produce the unstable triazoline 96 which undergoes a subsequent loss of nitrogen to give aziridine 97 that was ultimately converted to 98. 

Some of the most synthetically useful reactions are intramolecular cycloadditions. An intramolecular cyclopentenone cycloaddition led to the formation of the tricyclic aziridine 54, an intermediate for the preparation of the alkaloid ( )-cephalotaxine, in good yield (Scheme 6.25). The intermediate triazoline was not detected. A related synthesis of the aziridine 55 was used as a step in a synthesis of the alkaloid ( )-aspidospermidine. °... 

The synthesis of triazoles by 1,3-dipolar cycloaddition between azides and alkynes has been extensively studied recently with numerous synthetic applications in the field of click chemistry. However, the Huisgen cycloaddition between azides 39 and alkenes 40 (Scheme 41.9) although less studied offers interesting opportunities for the stereoselective formation of C N bonds in the context of natural products synthesis. The triazolines 41 thus formed are in fact good precursors of aziridines via ring contraction and expulsion of N2. 

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