Alkylation 1,2,4-triazolines

Alkyl-triazolines (4.17) were investigated more recently by the same group (Smith et al., 1993). These compounds may be considered as cyclized (Z)-triazenes. It was deduced from very similar dose-response curves for 1-methyltriazoline and 1-methylaziridine and from comparison of the activities of alkyltriazolines, alkyl-triazenes, and alkylaziridines that the ultimate mutagenic intermediate is the aziridinium ion 4.18 and not the diazonium ion (4-14). 

The values of X = NH, OH, F, Cl, and CH3 are smaller than that of X = H, in accordance with the observed selectivity. Excellent correlation was found for all other cyclopentadienes described above. Syn rr-facial selectivity in the reactions between 4-phenyl-l,2,4-triazoline-3,5-dione and cyclopentadiene having simple alkyl group at 5 positions are reported by Burnell and coworkers [46] (Scheme 37). 

Acyl hydrazides are useful precursors for the synthesis of 1,2,4-triazoles. Reaction of acyl hydrazides 149 with imidoylbenzotriazoles 148 in the presence of catalytic amounts of acetic acid under microwave irradiation afforded 3,4,5-trisubstituted triazoles 150 <06JOC9051>. Treatment of A-substituted acetamides with oxalyl chloride generated imidoyl chlorides, which reacted readily with aryl hydrazides to give 3-aryl-5-methyl-4-substituted[ 1,2,4]triazoles <06SC2217>. 5-Methyl triazoles could be further functionalized through a-lithiation and subsequent reaction with electrophiles. ( )-A -(Ethoxymethylene)hydrazinecarboxylic acid methyl ester 152 was applied to the one-pot synthesis of 4-substituted-2,4-dihydro-3//-1,2,4-triazolin-3-ones 153 from readily available primary alkyl and aryl amines 151 <06TL6743>. An efficient synthesis of substituted 1,2,4-triazoles involved condensation of benzoylhydrazides with thioamides under microwave irradiation <06JCR293>. 

Triazoline-3,5-dione 184 underwent an ene reaction with olefins 183 to yield trialkylated allylic urazoles 185, which were further elaborated into allylic amines 186 . DBU has been found to be a mild and convenient base for the alkylation of 1,2,4-triazole with various alkyl halides in the high yielding syntheses of 1-substituted-1,2,4-triazoles <00TL1297>. 

Numerous alkyl- and/or aryl-substituted 2(17/)-pyrazinones react with 47/-l,2,4-triazoline-3,5-dione to give high yields of [4-I-2] adducts <1998JHC655>. 

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). 

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. 

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... 

Alkyl- and l-aryl-5-hydroxytriazolines with two different substituents at C-4 exist in solution as an equilibrium mixture of two diastereomers,261,262 apparently as a result of the conversion of the triazoline to open-chain... 

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... 

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