1.2.4- Triazole-3,5-dione, 4-phenyl

Since both oxepin and its valence isomer benzene oxide contain a x-tb-diene structure they are prone to Diels-Alder addition reactions. The dienophiles 4-phenyl- and 4-methyl-4//-l,2,4-triazole-3,5-dione react with substituted oxepins at room temperature to give the 1 1 adducts 7 formed by addition to the diene structure of the respective benzene oxide.149 190,222... 

Reduction of the 1//-1,2-benzodiazepines 6 with lithium aluminum hydride results in the dihydro compounds 8, which are dehydrogenated to the 3H-1,2-benzodiazepines 9 by 4-phenyl-4//-l,2,4-triazole-3,5-dione.123 The products readily revert to the 1//-tautomers in the presence of sodium methoxide. 3//-1,2-Benzodiazepines react with 3-chloroperoxybenzoic acid to give mixtures of 1- and 2-oxides, 10 and 11, in which the latter predominate. Treatment of the 2-oxides 11 with nucleophiles provides 3-substituted H- 1.2-benzodiazepines 12. Selected examples are given.124... 

The condensed l//-l,2-diazepines 12 are transformed into the 3//-tautomers 24 by reduction with lithium aluminum hydride to give 23, followed by dehydrogenation with 4-phenyl-4//-1,2,4-triazole-3,5-dione.146... 

Substituted (5R,6A,)-6-(dimethyl(phenyl)silyl)-2-phenyldihydropyrazolo[l,2- ][l,2,4]triazole-l,3(2//,5//)-dione 716, synthesized via the [3+2] annulation of a-substituted allylic silanes 715 with PTAD, were oxidized to the corresponding hydroxy substituted urazoles 717. This work shows that allylsilanes with a single substituent at the allylic carbon undergo exclusive stereoselective [3+2] annulation (Scheme 114) <2007TL6671>. 

Cyclic ADC compounds are similarly prepared by oxidation of the corresponding cyclic hydrazine derivatives. The most commonly encountered compounds are the 3//-l,2,4-triazole-3,5(4//)-diones (5), and in particular the 4-phenyl derivative (5, R = Ph), usually abbreviated as PTAD. Similarly, the abbreviation MTAD is used for the 4-methyl derivative. First prepared by Thiele,18 PTAD remained unused in organic synthesis until Cookson reported its powerful dienophilic properties some 70 years later.19 PTAD is an isolable, red, crystalline compound, prepared by r-butyl hypochlorite oxidation of 4-phenylurazole.20 Other oxidants which have been successfully... 

UV irradiation of 2-arylbenzotriazoles (144), including the commercially available photostabilizer Tinuvin P, in an aerated solvent results in oxidation of the benzo ring to give the 2-aryl-l,2,3-triazole-4,5-dicarboxylic acid (146), possibly via the intermediate 2-arylbenzotriazole-4,7-dione (145) (Scheme 25). Indeed, when the independently synthesized l-phenyl-2. -benzotriazole-4,7-dione (145, R = = H) is irradiated under the same conditions, compound (146 R = R = H) is formed, and... 

Phenyl-3/7-l,2,4-triazole-3,5(4//)-dione (PTAD) has an extensive chemistry, largely as a dieneo-phile, and it will be treated separately. 

Another interesting synthesis of spiro[2.3]hexan-4-one (16) comprised of dipolar attack of 4-phenyl-l,2-dihydro-4//-l,2,4-triazole-3,5-dione on bicyclopropylidcnc to give a zwitterion 17, which underwent ring enlargement to 18 before ring closure to diaziridine 19 took place. Accordingly, in the presence of water, 18 was trapped with formation of spiro[2.3]hexan-4-one (16) which was also obtained from 19 by saponification.118... 

H-l,2,4-Triazole-3,5-dione, 4-phenyl- (8,9) (4233-33-4) tert-Butyl hypochlorite Hypochlorous acid, tert-butyl ester (8) Hypochlorous acid, 1,1-dimethylethyl ester (9) (507-40-4)... 

Condensation between pentan-2,4-dione and 4-phenyl[l,2,4]triazol-3-ylacetonitrile gives the highly substituted triazolopyridinium salt 56.70... 

Iodobenzyl propargyl ether 57 cyclizes with 7t-allylpalladium (Scheme 18) to form after trapping by a secondary amine tetrahydro-2-benzoxepines 58 in 70% yield. The piperidino derivative 58 (R2 = (CH2)5) undergoes Diels-Alder reaction with 4-phenyl-l,2,4-triazole-3,5-dione as dienophile to give a spiro derivative 59 in 44% yield <1996TL6565>. 

The synthesis of a new series of polyfused l,2,4-triazolo[3,4- ][l,3,4]thiadiazepines by reactions of 3-phenyl-5,6,7,8-tetrahydro[l,2,4]triazolo[3,4-A [l,3,4]thiadiazepine-6,8-dione 98 has appeared <2002PS2871 >. The starting material was obtained in good yield via the reaction of 4-amino-5-phenyl-l,2,4-triazole-3-thione 99 with malonyl... 

The 3-vinylbenzofurans 174 and 175 reacted in the normal fashion with the highly reactive dienophile 4-phenyl-l,2,4-triazole-3,5-dione (PTAD)... 

As l,2,4-triazole-3,5-dione (PTAD) is a stronger dienophile than acetylenic esters, more facile formation of the Diels-Alder cycloadducts was expected. But because it cannot behave as a diene in a reaction with alkynes such as diethyl azodicarboxylate, the formation of dihydrooxadia-zines is excluded. In spite of these characteristics, no Diels-Alder adducts were obtained in the reaction of l-phenyl-4-vinylpyrazole with PTAD in acetone at -80°C and 2,2-dimethyl-4(l-phenylpyrazol-4-yl)-8-phenyl-l,6,8-triaza-3-oxabicyclo[4.3.0]nona-7,9-dione 277 was obtained as a major product. The isolation of the tetrahydrooxadiazine 277 indicates that the 1,4-dipole 278 was formed and trapped with acetone. 

Hydrolysis of 2-phenyl-[l. 2.3]triazolo[4,5-d]pyrimidine-5,7-dione N-oxides 463 in basic solution gives rise to 4-amino- and 4-ureido-2-phenyl-l,2,3-triazole-5-carboxylic acid 1-oxides 464, as well as their hydrazides and methylamide (2005JGU636) (Scheme 134). 

Some unexpected results were obtained when deprotonation with LDA was followed by reaction with diethyl azodicarboxylate (Scheme 44). The ester 147 was isolated suggesting that this reagent could be considered as a C-electrophile rather than a N-electrophile. However, when this reaction was performed with a 4-monosubstituted /3-sultam, the expected N-addition products 148 were isolated. N-Addition occurs also with 4-phenyl-3/7-l,2,4-triazole-3,5(4/7)dione leading to compound 149 <2004HCA1574>. 

Another field of research is concerned with the one-pot synthesis of this system from readily available starting materials. In Scheme 12, reaction of phenyl azide and malononitrile in the presence of sodium ethoxide leads, via the intermediate triazole (139), to the self-condensation product (140), itself a triazolopyrimidine. In the presence of other nitriles the preferred formation of the more useful compounds (141) occurs in low to moderate yields with small amounts of dimer <87JHC997>. Direct synthesis of the 5,7-dione derivatives (143) (60-90%) is achieved by the reaction of the readily available aminopyrimidinedione (142) with an azide iminium salt in dichloromethane at moderately high dilution <87JHC1493>. 

Several syntheses of pyridazinopyridazines via Diels-Alder reactions of 4-phenyl-1,2,4-triazole-3,5-dione (PTAD) (27) with functionalized dienes have been described. One example is the reaction of the diene (26) with PTAD (27) to afford the tandem Diels-Alder adduct (30) (Scheme 5) <85JCS(P1)71>. 

I, maleic anhydride II, 4-phenyl-[1,2,4]triazole-3,5-dione ill, norbornene iv, 2,3-dihydrofuran (xs) ... 

Thiophene 1,1-dioxide did not undergo cycloaddition with electron-deficient dienophiles. In most of the cases the dihydrobenzothiophene derivative 109 was obtained as the major product. This shows that self-dimerization is faster than cycloaddition with a different molecule. In the case of dimethyl acetylenedicarboxylate (DMAD) and 4-phenyl-3//-l,2,4-triazole-3,5(4//)-dione (PTAD), the Diels-Alder adducts 111 and 112 of 109 were obtained <1997JA9077>. However, cyclopentadiene gave the Diels-Alder adduct 113 with thiophene 1,1-dioxide. The DMAD adduct 111 on thermolysis undergoes a retro-Diels-Alder reaction to give dimethyl phthalate and thiophene 1,1-dioxide. Azulene was isolated in the thermolysis of 108 in the presence of 6-(dimethylamino)-fulvene this was the result of a [4-1-6] cycloaddition of the thiophene 1,1-dioxide formed in the reaction followed by elimination of SO2 and dimethylamine (Scheme 28) <1999BCJ1919>. 

The most commonly employed diazenes, e.g., diethyl, bis(2,2,2-trichloroethyl), and di-/m-butyl diazenedicarboxylate, and 4-phenyl-3/7-1,2,4-triazole-3,5(4/7 )-dione, are commercially available. However, various new reagents or methods recently introduced for the preparation of specific diazenes from hydrazines can be successfully applied to other hydrazines. Especially important is the development of chemoselective methods for converting hydrazines to diazenes in the presence of unsaturated substrates, for example in intramolecular cycloaddition reactions (Section 7.2.10.3.10.2.), where either the (di)ene group and other functions present in the substrate are sensitive to the (oxidizing) reagent employed. 

On the other hand, the diazetidines 5 and 7 only are produced by the reaction of indene with phthalazine-l,4-dione (4)4 and 4-phenyl-3//-l,2,4-triazole-3,5(4//)-dione (6)1. The adduct 7 was successively converted to fra .v-(l,2-dihydro-3-hydroxy-2-indenyl)triazolidinone by acidic hydrolysis T Furthermore, the diazctine was prepared by a sequence involving hydrolysis of the triazolidine ring with concomitant decarboxylation, and oxidation of the intermediate diaze-tidine5. 

Reaction of Alkenes with 4-Phenyl-3//-l,2,4-triazole-3,5(4/A)-dione (6) in Methanol General Procedure" ... 

A solution of 4-phcnyl-3//-l.2.4-triazole-3,5(4//)-dione (6) in CH2C12 is added dropwise to a stirred solution of the alkene or diene in CHjOH at the desired temperature. After the characteristic red color of 4-phenyl-3A/-l,2,4-1 riazole-3,5(4//)-dione (6) has disappeared, the solution is stirred an additional 1-2 h. The solvent is removed at reduced pressure, and the products are separated by column chromatography on silica gel using mixtures of F.tOAc and hexane as eluant and recrystallized from EtOAc/hcxanc mixtures. 

Dialkyl diazenedicarboxylates do not undergo efficient cycloaddition with vinyl ethers. For example the [2 -I- 2] adduct was obtained in low yield from the cyclopropane-fused dihydropy-ran 11 even at high temperature28. From the same substrate the [2 + 2] cycloadduct with 4-phenyl-3//-1,2,4-triazole-3,5(4//)-dione was obtained quantitatively even at low temperature through a polar mechanism involving an aziridinium imide as the intermediate28. 

Phenyl- and 4-methyl-3//-1,2,4-triazole-3,5(4//)-diones have most commonly been employed, although a series of 4-substituted analogs (R = CH3, Et, r-Bu, Bn, 4-CH3OC H4, 4-N02C6H4, CSHSCH = N) have been prepared and the substituent and solvent effects in the Diels-Alder reactions with a variety of dienes determined27. The unsubstituted parent compound is less stable and as a result has been less frequently used22-24. 

The cycloaddition of 4-phenyl-3//-l,2,4-triazole-3,5(4/f>dione to ( ,Z)-1.3-cyclodecadiene, ( ,Z)-l,3-cyclononadiene, and (Z,Z)-l,3-eyclononadiene gives in each case a single isomer 3-5 by a concerted sm-addition mechanism, as demonstrated by single-crystal X-ray analysis28. 

The cycloaddition of 4-phenyl-3//-l,2,4-triazole-3,5(47/)-dione and 4-benzyl-3,4,5-trimethyl-pyrazole gives an approximately 1 1 mixture of diastereomeric products 7, which can be separated by crystallization and decomposed separately photochemically to 1,5,7-triazatricy-clo[3-3.0.02,4]octane-6,8-diones 861. 

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