3- Alkyl-substituted 1,2,3-triazole

Reactions of salts of 1,2,3-triazole with electrophiles provide an easy access to 1,2,3-triazol-jV-yl derivatives although, usually mixtures of N-l and N-2 substituted triazoles are obtained that have to be separated (see Section 5.01.5). Another simple method for synthesis of such derivatives is addition of 1,2,3-triazole to carbon-carbon multiple bonds (Section 5.01.5). N-l Substituted 1,2,3-triazoles can be selectively prepared by 1,3-dipolar cycloaddition of acetylene or (trimethylsilyl)acetylene to alkyl or aryl azides (Section 5.01.9). 

Both the parent compound and the alkyl-substituted thiazolo[3,2-h][l,2,4]triazoles show UV absorption between 240 and 250 nm. Some UV data of other derivatives are given in Table XV. 

Different synthetic routes have been used to prepare these carbenes (Scheme 8.6). The most common procedure is the deprotonation of the conjugate acid. In early experiments, sodium or potassium hydride, in the presence of catalytic amounts of either f-BuOK or the DMSO anion were used. ° Then, Herrmann et al. showed that the deprotonation occurs much more quickly in liquid ammonia as solvent (homogeneous phase), and many carbenes of type IV have been prepared following this procedure. In 1993, Kuhn and Kratz" developed a new and versatile approach to the alkyl-substituted N-heterocyclic carbenes IV. This original synthetic strategy relied on the reduction of imidazol-2(3//)-thiones with potassium in boiling tetrahydrofuran (THF). Lastly, Enders et al." reported in 1995 that the 1,2,4-triazol-5-ylidene (Vila) could be obtained in quantitative yield from the corresponding 5-methoxy-l,3,4-triphenyl-4,5-dihydro-l//-l,2,4-triazole by thermal elimination (80 °C) of methanol in vacuo (0.1 mbar). 

Another class of heterocyclic compounds are silyl-substituted triazoles which can be obtained by the addition of TMS-azide 14) and manifold substituted acetylenes 1, 35, 350 (Scheme 50)33,209 2ll Those in the first step resulting l-TMS-4-phenyl (3Ji)-, l-TMS-4,5-bis(methoxycarbonyl)- 352) and l-TMS-4-alkyl-l, 2,3-triazole 353) are then hydrolyzed to form 4-phenyl- 354)-, 4,5-bis(methoxycarbonyl)- 355), 4-alkyl-l,2,3-triazole 356). 

The 1,2,3-triazole 1-oxides 326 are usually stable, crystalline, semipo-lar, and colorless compounds. The lower 2-alkyl-substituted 1,2,3-triazole 1-oxides tend to be slightly hygroscopic. They act as very weak bases, protonation requiring acids like triflic acid and O-alkylation requiring tri-methyloxonium salts. No pKa values have been reported. 

Unlike hydrazoic acid, trimethylsilyl azide is thermally quite stable. Even at 200° it decomposes slowly and without explosive violence. Accordingly it is a very convenient and safe substitute for hydrazoic acid in many reactions. A notable example is the cycloaddition of hydrazoic acid to acetylenes which is a general route to substituted triazoles.4 The reaction of trimethylsilyl azide with acetylenes is also a general reaction from which the 2-trimethyIsilyI-1,2,3-triazoles may be obtained in good yield.5 On hydrolysis these adducts are converted under mild conditions to the parent alkyl 1,2,3-triazoles.5... 

The method has also been applied to the synthesis of alkyl-substituted quinoxalin-2-amines. Thermal rearrangement of l-(2-aminophenyl)-4,5-dihydro-5-morpholino-l,2,3-triazoles 15 affords unstable 2-alkyl-l,2,3,4-tetrahydroquinoxalin-3-amines, which undergo deamination and consequent oxidation to afford 2-alkylquinoxalines 16. ... 

The first of the 8-azapurines, 1,3-dimethyl-8-azapurin-2,6-dione (1), was made at the start of this century by Wilhelm Traube, who cyclized the corresponding 4,5-diaminopyrimidine with nitrous acid. Similar syntheses from pyrimidines, although excluding any possibility of placing an alkyl substituent in the 7 or 8 position, dominated the field until 1968 when appropriately substituted triazoles were introduced to overcome these limitations. These two approaches to the preparation of 8-azapurines, from pyrimidines or from triazoles, are expanded in Sections IV,A and B, respectively. 

In 1968, the scope of the formamide condensation was greatly expanded by discovery of practical syntheses for the 1- and 2-methyl derivatives of 4-amino-1,2,3-triazole-5-carboxamide. These, for the first time, made possible the direct preparation, and in excellent yields, of 7- and 8-alkyl-substituted 8-azapurines. These new triazoles also underwent condensation with (an excess of) urea and thiourea (175°C, 1 h, no solvent) to give the correspondingly methylated derivatives of 8-azapurine-2,6-dione (64-89% yield) and 2-thioxo-8-azapurin-6-one (55% yield), respectively. ... 

An example of alkylation of a 3-substituted triazole is shown below ... 

An alternative method for preparing the dialkyl triazole sulfonyluieas 20 involved alkylation of monoalkyl-substituted triazole sulfonyluieas which were prepared as shown. In this case, reaction of hydrazine with the cyanoimidate 16 gave rise to only one aminotriazole product 19. Subsequent alkylation of the derived sulfonylurea afforded the dialkyltriazole sulfonylureas 20. 

For both azole and benzazole rings the introduction of further heteroatoms into the ring affects the ease of quaternization. In series with the same number and orientation of heteroatoms, rate constants increase in the order X = 0requires stronger reagents and conditions methyl fluorosulfonate is sometimes used (78AHC(22)71). The 1-or 2-substituted 1,2,3-triazoles are difficult to alkylate, but methyl fluorosulfonate succeeds (7IACS2087). 

Thiadiazoles are quaternized to give 3- or mixtures of 2- and 3-alkyl quaternary salts. In 5-amino-1,2,4-thiadiazole, quaternization takes place at the 4-position (90) (64AHC(3il). 1-Substituted 1,2,4-triazoles are quaternized in the 4-position (91), and 4-substituted 1.2,4-triazoles are quaternized in the 1- or the 2-position (92) 64AHC(3)l). 

Abbreviations aapy, 2-acetamidopyridine Aik, alkyl AN, acetoniuile Ar, aryl Bu, butyl cod, 1,5-cyclooctadiene COE, cyclooctene COT, cyclooctatetraene Cp, cyclopentadienyl Cp , penta-methylcyclopentadienyl Cy, cyclohexyl DME, 1,2-dimethoxyethane DME, dimethylformamide DMSO, dimethyl sulfoxide dmpe, dimethylphosphinoethane dppe, diphenylphosphinoethane dppm, diphenylphosphinomethane dppp, diphenylphosphinopropane Et, ethyl Ec, feirocenyl ind, inda-zolyl Me, methyl Mes, mesitylene nb, norbomene orbicyclo[2.2.1]heptene nbd, 2,5-norbomadiene OTf, uiflate Ph, phenyl PPN, bis(triphenylphosphoranylidene)ammonium Pi , propyl py, pyridine pz, pyrazolate pz, substituted pyi azolate pz , 3,5-dimethylpyrazolate quin, quinolin-8-olate solv, solvent tfb, teti afluorobenzobaiTelene THE, tetrahydrofuran THT, tetrahydrothiophene tmeda, teti amethylethylenediamine Tol, tolyl Tp, HB(C3H3N2)3 Tp , HB(3,5-Me2C3HN2)3 Tp, substituted hydrotiis(pyrazol-l-yl)borate Ts, tosyl tz, 1,2,4-triazolate Vin, vinyl. 

Another important click reaction is the cycloaddition of azides. The addition of sodium azide to nitriles to give l//-tetrazoles is shown to proceed readily in water with zinc salts as catalysts (Eq. 11.71).122 The scope of the reaction is quite broad a variety of aromatic nitriles, activated and nonactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction. The reaction of an arylacetylene with an azide in hot water gave 1,4-disubstituted 1,2,3-triazoles in high yields,123 while a similar reaction between a terminal aliphatic alkyne and an azide (except 111 - nitroazidobenzcnc) afforded a mixture of regioisomers with... 

A variety of triazole-based monophosphines (ClickPhos) 141 have been prepared via efficient 1,3-dipolar cycloaddition of readily available azides and acetylenes and their palladium complexes provided excellent yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides <06JOC3928>. A novel P,N-type ligand family (ClickPhine) is easily accessible using the Cu(I)-catalyzed azide-alkyne cycloaddition reaction and was tested in palladium-catalyzed allylic alkylation reactions <06OL3227>. Novel chiral ligands, (S)-(+)-l-substituted aryl-4-(l-phenyl) ethylformamido-5-amino-1,2,3-triazoles 142,... 

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>. 

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