Triazolines synthesis

Oximino cyanoacetate or malonate esters (Me02CC(CN)=N0Ts or (Me02C)2C= NOCOPh) reacted with diazoaUcanes (RCHN2) to give unstable 1,2,3-triazolines . Synthesis of Al-imidoylbenzotriazoles via benzotriazole-mediated Beckmann rearrangement of oximes is also described . ... 

Although several early reviews provide brief discussions on olefin-azide additions,6-9 the greater part of the work on imine-diazoalkane reactions is more recent and not covered previously.10,11 The major methods of triazoline synthesis are outlined in a recent treatise on 1,2,3-triazoles.13... 

Although the olefin-azide and the imine-diazoalkane reactions constitute the two major general routes to triazoline synthesis, there are several other interesting pathways that have not been explored sufficiently and hence have only limited application. 

Enamine formation occurs by the thermolysis of diazo compounds (Scheme 150)67 109,278 284 288,304 332 453 454 via a carbene-like intermediate.284 332 When R1 = Ph, it enters into competition with hydrogen migration,284,332 and the electrophilic character of the carbene enhances the migration of the dimethylaminophenyl more than the phenyl.332 When triazoline synthesis is carried out at temperatures higher than that at which thermolysis of diazo compounds occurs, enamines are obtained exclusively, as in the addition of phenyl azide to cinnamic nitriles and ketones, with phenyl migration dominating in the nitrile.284 Enamine is also formed quantitatively in the reaction of ethyl diazoacetate with benzylideneaniline at 110°C.455... 

The 1,2,4-triazoline ring system can be constructed from reactions of acyclic compounds or from transformation of cyclic structures. In the classical approach to triazoline synthesis, the N—C—N—N skeleton of... 

Methylhydrazino-1,4-benzodiazepine 17 reacts with acetaldehyde to yield the dihydrotriazolobenzodiazepine 18, along with a hydrazide, 19, suspected to be a secondary product from air oxidation of 18. The 1-methyl isomer (16), however, gives a Schiff base (20), similar to the one obtained in the Busch reaction (10MI1) for triazoline synthesis (Scheme 3) (79JOC2688). 

The full synthetic potential of nitrile ylides in 1,2,4-triazoline synthesis has not yet been explored the few available studies are confined to reactions with symmetrical dipolarophiles. Substituent effects of unsymmetri-cal dipolarophiles on the regiochemistry of triazoline formation are not known. 

Aromatization to triazoles by the elimination of stable molecules is common among the 1,2,4-triazolines. The reaction occurs spontaneously or under the influence of heat, acid, or base, which invariably forms part of the reaction conditions under which the triazoline synthesis usually takes place. Thus, in many cases, the only reaction products are triazoles. 

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. 

The synthesis of 5-phosphono-l,2,4-triazolin-3-one 137 began with the low-temperature metalation and phosphorylation (77) of the f-butyldimethylsilyl (TBDMS)-protectedlV-benzyl-tiiazolinone 134. The phosphonate diester 135 was obtained ter the silyl protecting group... 

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]. 

Rejzek, M., Stockman, R.A., van Maarseveen, J.H., Hughes, D.L. (2005) Combining Two-Directional Synthesis and Tandem Reactions Desymmetrisation by Intramolecular Cycload-dition/Triazoline Fragmentation. Chemical Communications, 4661 662. 

Azines have been prepared by initial condensation of diethoxyphosphinyIhydrazine anions with aldehydes or ketones (Scheme 9). Phosphoryl azides undergo 1,3-dipolar cycloaddition to 2-tetralone enamines to give triazolines, possibly en route to amidines. A full paper on the addition of diethyl dibromophosphoramidate to alkenes(leading to the synthesis of 2-bromoalkylamines) has appeared. ... 

In 1974, Vogel and his coworkers62) reported the first synthesis of the syn-benzene bisepisulfide 119 and its thermal behavior. The bisepisulfide 119 is thermola-bile and decomposes at 20 °C with a half-life of about 30 min to form benzene and sulfur as final products. When the reaction was carried out in the presence of 4-phenyl-1,2,4-triazoline-3,5-dione (PTD), 119 gave the product 120 which corres-... 

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>. 

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). 

A simple procedure for the synthesis of 4,5-disubstituted 1,2,3-triazoles 1247 involves stirring a mixture of nitroethene 1245 with trimethylsilyl azide and tetrabutylammonium fluoride at 30 °C for 3h. No solvent is needed. Triazoline 1246, which forms in the first step of the reaction, eliminates nitrous acid, and the trimethylsilyl group is cleaved off by the fluoride anion to afford triazole 1247. Various aryl and heteroaryl substituents R are used providing triazoles 1247 in 70-90% yield (Scheme 207) <2005JOC6526>. 

The synthesis of 4,5-disubstituted triazoles shown in Scheme 208, carried out on a polymer support with microwave assistance, is based on a similar principle. In the first step, sulfinate 1248 is converted to sulfone 1249. Condensation with aldehydes provides vinyl sulfones 1250. Cyclocondensation of sulfones 1250 with sodium azide generates corresponding triazoline intermediates that eliminate sulfinate 1248 to provide triazoles 1251 in moderate to good yield <2006OL3283>. 

The synthesis of imidazo[2,Tc][l,2,4]triazolo-3-thiones has been investigated. For instance, the reaction of 1,2,4-triazoline-3-thione 361 <1995JHC275> with methyl trifluoromethanesulfonate affords the stable 3-methylmercapto-1,2,4-triazolium trifluoromethanesulfonate 362 in quantitative yield, which after treatment with sodium bicarbonate and bromine provides 6-bromomethyl-2,6-dimethyl-7-ethoxycarbonyl-2,3,5,6-tetrahydro-7//-imidazo[2,T4-[l,2,4]triazolo-3-thione 10 in 47% yield, via intermediate 363 (Scheme 36) <1996T791>. 

NITR0CYCL00CTENE, 50, 84 Nitrogen atmosphere, apparatus for maintaining, 52, 46 Nitrogen, purification, 50, 69 1-Nitro-l-octadecene, 50, 86 o-Nitrophenylacetaldehyde dimethyl acetal, 52, 139 4-p-Nitrophenyl-l,2,4-triazoline- 3, 5-dione, synthesis of, 51, 125... 

Although these two methods have found widespread application for the synthesis of free carbenes, they failed for selected saturated imidazolidin-2-ylidenes and especially in the preparation of triazolin-5-ylidenes. In these cases the free carbene species 7 can be obtained from 2-alkoxyimidazolidines 6 [44] or 5-aUcoxytriazoles [36] by thermally induced ot-elimination of an alcohol (Fig. 5). In addition to 2-aUcoxyimidazolidmes, 2-(pentafluorophenyl)imidazolidines [45, 46] have also been used for the generation of NHCs by cx-elimination. The adduct 8 eliminates acetonitrile upon heating [47] to yield the benzimidazolin-2-ylidene 9. In a more exotic procedure, imidazolium salts have been reduced electrochemically to give the free imidazolin-2-ylidenes [48]. 

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