Dihydrotriazoles

Discussion of these compounds is divided into isomers of aromatic compounds, and dihydro and tetrahydro derivatives. The isomers of aromatic azoles are a relatively little-studied class of compounds. Dihydro and tetrahydro derivatives with two heteroatoms are quite well-studied, but such compounds become more obscure and elusive as the number of heteroatoms increases. Thus dihydrotriazoles are rare dihydrotetrazoles and tetrahydro-triazoles and -tetrazoles are unknown unless they contain doubly bonded exocyclic substituents. 

Quantitative formation of 118-phenyldihydrotriazole (II) by heating Compound 118 with an excess of phenyl azide liquid, in absence of solvent, and then removing unreacted azide with a mechanical vacuum pump. (Because of the small amounts of 118 and phenyl azide reacting, the presence of conveniently measured amounts of solvent makes the rate of dihydrotriazole formation too slow to be practicable.)... 

A stock solution of the triazole in hexane was made up and diluted to various strengths, and 1.0-ml. aliquots of the diluted solutions were carried through the procedure described below. The transmittance of the colored solutions obtained from 10 to 50 micrograms of the 118-phenyldihydrotriazole was plotted against concentration to make a standard curve. In subsequent analyses, the amount of Compound 118 is readily calculated from the amount of dihydrotriazole formed. 

Procedure. A hexane solution of Compound 118 is diluted or concentrated so as to bring the 118 content within a range of 15 to 150 micrograms per ml. In cases where the hexane solution requires concentration, the evaporation is carried out in a beaker on a steam bath with a gentle stream of air passing over the surface. The concentrated or diluted solution of 118 is washed with hexane into a volumetric flask and made up to volume with the hexane washings. One milliliter of the adjusted Compound 118 solution is precisely measured into a spectrophotometer cell, 2 drops of phenyl azide are added, and the dihydrotriazole is quantitatively formed and then treated with diazotized dinitroaniline to produce the red color as in the preparation of the standard curve. A blank, starting with 1.0 ml. of hexane and 2 drops of azide, is run at the same time. 

The transmittance readings should be taken within 5 to 10 minutes after red color development. The developed red color is stable on standing up to at least 2 hours when working with crystalline dihydrotriazole only however, when phenyl azide is used, as it must be in an actual analysis for Compound 118, some of its nonvolatile thermal decomposition products develop colors on standing. 

From the manipulative standpoint, the critical step lies in the vacuum evaporation of the solvent from the solution of Compound 118 and the two drops of phenyl azide. Care must be observed that no foaming or undue chilling occurs during the evaporation undue chilling may cause some Compound 118 to crystallize out of contact with the phenyl azide and prevent quantitative formation of the dihydrotriazole. 

The application of vacuum and its release must at all times be gradual, so that none of the crystalline Compound 118 or its dihydrotriazole is swept out by a surging air stream. A two-way stopcock may be conveniently used for this purpose. 

Dipolar addition to alkenes also occurs with species other than ozone, often to give products much more stable than the labile molozonides (54), e.g. addition of azides (61) to give dihydrotriazoles (62) ... 

Treatment of 5-methylene-3,3-dimethyl-3,4-dihydrotriazole (77) with acrylonitrile gave aza-spiro[3.2]hexane (78) as a 1 1 mixture of diastereomers (Equation (25)) <86CC172l>. 

The lithiated hydrazone (130) reacts with the salt (131) to give the amidrazone (132) in 35% yield. Oxidation of (132) with lead tetraacetate gives the 3,4-dihydrotriazole (133) (Scheme 26) <86CC1721 >. 

Pyrazoline 68 is converted into the V-acetyl derivative 69 by treatment with acetic anhydride and triethylamine at —5 °C (Scheme 5). Treatment of 68 with acetic acid at 40 °C caused decomposition of the dihydrotriazole ring to give the enamine 71 <1997TL5891>. Treatment with trifluoroacetic acid in dichloromethane at room temperature, however, caused decomposition of both the dihydrotriazole and the oxazolidine rings yielding the pyroglutaminol 70 <2001J(P1)2997>. 

Dihydrotriazoles, 135, undergo a pyrolysis reaction to generate a mixture of pyranopyrroles, 136, and amidines, 137 (Equation 70). 2-Aminoaziridines are proposed as key intermediates in the sequence <2001J(P1)1723>. Choice of solvent has a significant effect on the ratio of 136 137 produced. 

The hydrolytic decomposition of 1-alky 1-4,S-dihydrotriazoles in aqueous buffers leads predominantly to 1-alkylazir-idines with lesser amounts of 2-(alkylamino)ethanol, alkylamines, and acetaldehyde. The rate of hydrolysis of 1-alkyltriazolines is about twice as fast as that of the analogous acyclic 1,3,3-trialkyltriazenes and varies in the order ArT-butyl > isopropyl > ethyl > butyl > methyl > propyl > benzyl. The proposed mechanism, involving rate-limiting formation of a 2-(alkylamino)ethyldiazonium ion 487, is shown in Scheme 103. 

Depending on the nature of the organic azide and of the alkene, as well as on the reaction conditions, a 1,3-dipolar cycloaddition can occur to give 4,5-dihydro-l,2,3-triazoles5"8. Most of the dihydrotriazoles are isolated and successively decomposed to aziridines either thermally or photochemically. However, sometimes the dihydrotriazoles are unstable and the aziridines are obtained directly156. 

Generally, the aziridines prepared by the nitrene or dihydrotriazole routes are used as precursors of /(-functionalized amines through ring-opening reactions, but in certain cases the dihydrotriazoles can be directly converted to /3-functionalized amines8b l57. 

Dihydrotriazoles with an electron-withdrawing or phenyl group (X) at C-4 together with a free hydrogen isomerize to give ring-opened / -diazo amines either spontaneously or under the action of a base7. 

Due to the complexity of the reaction pathways and the diversity of the products obtained, a methodical presentation of the subject matter is not easily accomplished the reactions of alkenes are conveniently separated from those of 1,3-dienes. Secondly, the reactions of alkenes are divided according to the nature of the azide partner that is equivalent to the nature of nitrogen substituent in the final product. Furthermore, when the intermediate dihydrotriazoles are isolated from the reaction mixture, the attention is focused on the products derived from successive decomposition. 

Starting from the Diels-Alder adduct 13, dihydrotriazoles were prepared by cycloaddition with /m-butyloxycarbonyl azide and successively converted to aziridines 14 and 15 and trans-aminolactone 1653. Although dihydrotriazoles generally gave mixtures of products by acidic treatment, it is possible to achieve the clean conversion to ring-opened products without the preliminary decomposition to aziridines. 

In general, the dihydrotriazoles were isolated and successively converted to the aziridine. Using this procedure the aziridination of electron-poor alkenes was also possible. The diastereoselec-tivity was satisfactory with diethyl ( )-2-butenedioate74 76, e.g., formation of 5, but from the (Z)-isomer a mixture of diastereomers and byproducts was obtained76. 

Preparation of the dihydrotriazole from ( )-crotonate and phenyl azide, which was unsuccessful under normal conditions74, was achieved under high pressure, although the a-amino diazo compound was the prevalent product78. IV-Aryl succinimides were suitable substrates for... 

Dihydrotriazoles were prepared diastereoselectively by cycloaddition of aryl azides to enol ethers and, under controlled conditions, enamines6-7. In only a few cases were the aziridines prepared by photochemical decomposition of thus formed dihydrotriazoles 84-85. 

The cycloaddition of aryl, benzyl, and 1-phenylethenyl azides to strained bicyclic alkenes, e.g., norbornene, and their substituted derivatives afforded generally the exro-dihydrotriazoles 17, which on photolytic decomposition afforded cleanly the exro-aziridines 233,42-48,70,93. Thermal decomposition of the dihydrotriazoles resulted in a complex mixture of products, including both exo- and entfo-aziridine and the imine95,96. 

The dihydrotriazoles prepared by cycloaddition of aryl, heteroaryl, and alkyl azides to 3,4-di-azatricyclo[4.2.1.02,5]nona-3,7-diene and 3,4-diazatricyclo[4.2.1.02,5]non-7-ene derivatives were smoothly converted to exo-aziridines by treatment with catalytic amounts of adds (acetic, trifluoroacctic, sulfuric) in aprotic solvents (diethyl ether, dichloromethane, dioxane) at 25-80°C for 4-48 hours, e.g., the sequence 9 -> 10 -> 11 or 12 -> 13 -> 14. The aziridines were further converted to (6-halo and (6-hydroxy aminesl03b. 

Hydroxy and /2-acetoxy (V-phenylamines were prepared in 50-97 % yield by ring opening of the /V-phenylaziridines prepared from strained bicyclic alkenes104. /3-Functionalized amines were sometimes obtained directly from the dihydrotriazoles, e.g., formation of 15 and 16. 

The highly strained twist" and chair bicyclic trans-cyclooctenes 17 and 18 underwent an exceptionally regioselective and diastereoselective cycloaddition with phenyl azide, the stereochemistry of the dihydrotriazoles was fully retained in the thermal decomposition to aziridi-nes107. Furthermore no imine is produced. 

The optically active aziridine ( + )-20 was prepared from (—)-(Z)-cyclooclene, via the dihydro-triazole (+)-1981. Similarly, the optically active dihydrotriazole was obtained in low yield, from partially resolved, optically active 1,2-cyclononadiene109. These results are consistent with a concerted cycloaddition mechanism. 

Excellent or complete diastereoselectivity was observed in cycloaddition of aryl azides with 5-alkoxy-2(5/f)-pyrrolones112. The dihydrotriazoles were obtained as a mixture of regioiso-mers 23-26 and converted photolytically to the aziridines in almost quantitative yields, although photolysis was performed only in an H-NMR tube. The thermal decomposition of the dihydrotriazoles in refluxing dimethylformamide gave a mixture of diastereomeric aziridines and enamines. Complete diastereoselectivity was provided by the cycloaddition of 4-methoxy-phenyl azide with 5-ethoxy-2(5//)-furanone to give 27 and 28112. 

The cycloaddition of aryl azides to the 17-substituted steroid- 16-enes occurred from the a-face to give a mixture of dihydrotriazole and aziridine derivatives, in a ratio which depends on the nature of the substituent at C-17113. With a methoxy substituent only the dihydrotriazole was obtained, but with a cyano substituent, the aziridine was the major product (4 1). No efforts were made to fully convert the dihydrotriazoles to the aziridines. 

The intramolecular 1,3-cycloaddition of azidoalkyl cyclohexenones occurred smoothly when the temperature range was between 80-110 °C, however, aziridines were obtained from the intermediate dihydrotriazoles il the correct substitution pattern and regiochemical arrangement were present, cf. formation of 13 and 14 vs. IS131,132. The reaction was applied to the formal total synthesis of ( )-desamylperhydrohistrionicotoxin132. Direct nitrene enone addition can not be ruled out when the reaction is performed in refluxing xylene. 

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