Triazolines => alkyl azides

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. 

Similarly to the reaction with diazomethane, [3 + 2] cycloaddition of alkyl azides to C70 affords three constitutionally isomeric adducts (87, 88, and ( )-89) 46.226,227 Thermal elimination of N2 from the fullerene-fused triazolines showed a preference for the formation of 6-5 open azahomofullerene structures (types 90 and ( )-91) as compared to the 6-6 closed aziridine isomers corresponding to 92 and 93 (Scheme 1.9).226,227... 

Safety Note. Because acyclic triazenes are potent biological alkylating agents, it is only prudent to assume that triazolines are also potentially toxic and carcinogenic. Efficient hoods and protective clothing should be used in working with these substances. Alkyl azides are treacherously explosive and should be treated with extreme caution. Wherever possible these compounds should only be handled as solutions. 

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. 

More recently published ideas include the formation of solid derivatives of alkyl azides by treatment with acetylene dicarboxylic acid to form 1-alkyl-triazole-4,5-dicarboxylic acids. These frequently form hydrates with poor melting points and generally poor analytical properties. Alternatively, one can obtain bicyclic fused-ring triazolines by treatment with norbornadiene or dicyclopentadiene °. 

Five-membered rings have tilso been obtained from unsaturated alkyl azides. Heating of 5-azido-5-methyl-l-hexene (149) yielded a mixture of 2,5,5-trimethyl-1-pyrroline (151) and 2,2-dimethyl-1-aza-bicyclo[3,l,0]hexane (152) (total yield 70%, products ratio 2-2 1). This reaction however proceeds via the isolable triazoline 150 and no nitrene intermediates are involved... 

The addition of alkyl azides to Ceo proceeds similarly via intermediate triazolines 9, which after extrusion of N2 rearrange to [5,61-adducts 10 as major and the [6,6]-adducts 11 as the minor monoaddition products. [3, 4,... 

Irradiation of the pyrazoline mixture 12, 13, and ( )-14 yielded methanofullerenes 15 and 16 (7 1) with a closed transannular 6 - 6 bond besides minor amounts of a third constitutional isomer (17), whereas thermolysis of the same mixture gave 17 and inherently chiral ( )-18 (4 l),both constituting core-modified fullerenes [76] (Scheme l).With open transannular 6-5 bonds , the functionalized regions of 17 and ( )-18 resemble methanoannulene sub-structures. [3 + 2]Cycloaddition of alkyl azides to C70 affords triazolines which are isolable when the temperature does not exceed ca. 50 °C. Similar to the reaction with diazomethane, three constitutionally isomeric adducts were observed [77,113], and the regioisomer of type 19 [113] with the substituent of the heterocycle located above the apex of C70, predominated over its regioisomer of type 20 in two in-... 

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). 

About 15 years ago, Aube et al. reported that alkyl azides undergo Lewis acid-mediated reactions with ketones 76 to give the corresponding lactams 78 via 77 (Azido-Schmidt reaction Scheme 14A) [44-48]. However, this reaction pathway does not proceed when a,/3-unsaturated ketones are used. It was recently shown that Lewis acid-activated enones like 79 undergo a [3-P2] cycloaddition with alkylazides, likely via an 1,2,3-triazoline intermediate 80, to give the corresponding enaminone 80 (Scheme 14B) [49]. 

It is tempting to think that allylic cations would behave similarly to other stabilized cations in their reactions with alkyl azides. " In practice what happens is invariably an initial formal [3+3] cycloaddition of azide to the allylic cation, which is followed by a migration event (typically of hydride) or trapping by a nucleophile. Pearson and coworkers found that when sulfonylindole 27 was treated with SnCk at -78 °C, followed by basic workup, triazoline adducts 28 were obtained as mixture of chloride epimers (Scheme 7.24). When A -alkyl indoles (e.g. 29) were subjected to Lewis acidic conditions, tri-azines such as 30 were obtained as the sole products. In the former case involving an iV-sulfonyl indole, a [3+2] cycloaddition pathway explains the product, whereas the iV-alkyl indoles examined underwent [3+3] cycloaddition. 

Weinreb and co-workers (16) reported a high-pressure-induced 1,3-dipolar cycloaddition of alkyl and phenyl azides with electron-deficient alkenes at ambient temperature. As a representative example, phenyl azide underwent cycloaddition with methyl crotonate (69) at 12 kbar to give the triazoline 70 (43%) and the p-amino diazoester 71 (53%). The high-pressure conditions resulted in high yield and a shorter reaction time (Scheme 9.16). 

Alkynes react with alkyl and aryl azides to give 1,2,3-triazoles (389 — 390). Suitable phosphoranes behave similarly thus (391) with cyanazide N3CN provides the 1,2,3-triazole-1-carbonitrile (392). Alkenes which are activated by electron-withdrawing groups, or are strained, give 1,2,3-triazolines (393) with azides. 

Cyanogen azide reacts with olefins at 0-35° to afford alkyl-idene cyanamides and/or N-cyanoaziridines arising from decomposition of an intermediate unstable triazoline. 54 With norbomadiene the isolated product is N-cyano-3-azatricyclo-[3.2.1.0s-4-M<,]oct-6-ene (58) which is unstable and rearranges into N-cyano-2-azabicycIo[3.2.1]octa-3,6-diene (59).167... 

Heterocyclic azides react with enamines31 1,8-naphthyridine azides give isolable triazolines.220 The bicyclic enamine 2-N-morpholinonorbornene with aryl and benzoyl azides furnishes stable, crystalline aminotri-azolines.39,213 Likewise, alkyl azidoformates yield stable triazolines.30,221... 

Stable triazolines are obtained from aryl azides and V-alkyl and N-aryl maleimides (Scheme 81 )307-309a the reaction succeeds with silyl azides310 and is utilized in the synthesis of polymers from bisazides and bismaleimides.311 312 Unlike maleimides, maleic anhydrides do not yield stable triazolines with trimethylsilyl azide the reaction products are oxazinediones (Section IV,A).310,313,314... 

The addition of alkyl or aryl azides to dimethylsulfoxonium methylide provides a safer alternative route to the synthesis of N-monosubstituted triazolines (Scheme 108).375-377 However, the generality of the method is limited because p-nitrophenyl and benzoyl azides yield only the vinyltriazenes (43) in order for triazoline cyclization to occur, the azide nitrogen bearing the substituent group should be sufficiently nucleophilic (see Scheme 108). 

Spontaneous isomerization of triazolines to diazo compounds can lead to addition of the latter to a second molecule of olefin, especially in the case of acrylic derivatives, resulting in a A pyrazoline, which by proto tropic rearrangement, gives the A2-compound (Scheme 149). Pyrazolines have been observed in the reactions of alkyl,67 aryl,32,282 heterocyclic,283,453 and gly-cosyl288 azides. A A pyrazoline is reported from the addition of phenyl and tosyl azides to 3,3-dimethylcyclopropene in this case the diazoimine formed by a retro-1,3-addition of the primary cyclopropanotriazoline adduct reacts with another olefin molecule.82... 

The first synthesis of the parent compound of the benzo[4,5]thieno[2,3-c]pyrrole ring system 99 [27] and its derivatives was accomplished using the same synthetic sequence (Scheme 16). Starting with 2-mcthyl benzolb thiophcnc-3-carbaldehyde 100, an intermediate 101 was obtained. Treatment of bromo compound 101 with sodium azide in ethanol led to the stable triazoline 102.1,3-Dipolar cycloreversion of 102 was induced by a catalytic amount of p-TsOH to give the parent 27/-benzo [4,5]thieno[2,3-c]pyrrole 99. Alternatively, direct treatment of bromo compound 101 with excess ammonia furnished 99 in one step. Compound 99 was treated with Boc20 and DMAP to give the /V-Boc derivative 103. Reaction of 101 with alkyl- and arylamines, respectively, afforded the N-substituted benzo[4,5]thieno[2,3-c]pyrroles 105 via a retro-malonate addition from intermediate 104. 

---