Halo-1,2,3-Triazoles

Only a single example of a fluoro-1,2,3-triazole has been reported in the literature (Eq. 1), and certainly additional study of these compounds and the defluoronating reagent 9.1-1 is warranted. 

Both direct and indirect syntheses of chloro-l,2,3-triazoles have been carried out. In the former approach, the reagent employed exerts an important influence on the product yield (Eqs. 2,3). A large number of additional combinations were tried but without synthetically useful results. It has also been shown that cyanogen chloride reacts with trimethylsilyl-diazomethane to give chloro-1,2,3-triazoles (Eq. 4) in fair yield. 

A somewhat broader range of reactions has been explored for the synthesis of bromo-1,2,3-triazoles. Two reports of the direct bromination show the efficiency of such reactions (Eq. 5). The reaction of 9.1-2 (Y = H) with two equivalents of sodium hypobromite also gives a very high yield of 

5-dibromo-l,2,3-triazole, and the bromination of alkyl-1,2,3-triazoles produces fair product yields (Eq. 6,7). It should be noted that 1-benzyl-1,2,3-triazole gives only a 33% yield of the 4-bromo product.  

The addition of azides to unsaturated bromo compounds has not produced exceptional yields (e.g., Eqs. 8,9). In view of the general success of such methods these examples should be studied further. 

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In contrast to other azoles whose stability decreases from A-iodo to A-bromo and further to A-chloro derivatives, l-chloro-3-nitro-l,2,4-triazoles are more stable that their 1-bromo and 1-iodo analogs. In this series the stability order is reversed (96UP1). Rearrangement of A-halo-1,2,4-triazoles is described in Section IV,B,2. 

Rearrangement of V-halo-l,2,4-triazoles to C-haloderivatives is described in a series of reports. The possibility of formation of C-halo-1,2,4-triazoles depends on the reactions conditions on the nature of the halogen and on the presence, type, and location of substituents at the carbon atoms of the ring. 

Pevzner MS, Trifonov RE (1998) Theoretical study of the structure of N-halo-1,2,4-triazoles. Russ J Org Chem 34 742-743... 

An interesting study reported in 2001, although it did not utilize any inverse-detected 2D NMR data, did report a wealth of useful chemical shift data for parent azoles and benzazoles. Solid-state chemical shift data were reported for several pyrazole analogues by Alvarez-Larena. Trofimenko et al reported a study of the buttressing effects of the A-tert-h xiy group of a series of pyrazoles in the solid state, followed by a study by Claramunt and co-workers of a series of halo triazoles. Martins and co-workers reported data for a series of 5-trichloromethyl-1,2-dimethyl-1/f-pyrazolium chlorides. Malpass and co-workers reported direct observe chemical shift data for a series of bicyclic amines and lactams. Recently, a large body of chemical shift data for a series of l,4-diazaspiro[4.5]decanes and l,4-oxazaspiro[4.5]-decanes using direct observe methods were reported by Ariza-Castolo and co-workers. " Readers with an interest in the chemical shift behavior of these systems are directed to these references as a source of data. 

Propiolaldehyde diethyl acetal has found numerous synthetic applications in the literature which may be briefly summarized. The compound has been utilized in the synthesis of unsaturated and polyunsaturated acetals and aldehydes by alkylation of metal-lated derivatives, " by Cadiot-Chodkiewicz coupling with halo acetylenes, " and by reaction with organocuprates. Syntheses of heterocyclic compounds including pyrazoles, isoxazoles, triazoles, and pyrimidines have employed this three-carbon building block. Propiolaldehyde diethyl acetal has also been put to use in the synthesis of such natural products as polyacetylenes " and steroids. ... 

The most widely used method for the ring closure to the title ring system is the reaction of a 3-mercapto-4-amino[l,2,4]triazole compound with an a-halo-oxo reagent. The particular realizations of these syntheses are summarized in Table 4. Comparison of the reference lists shows that reactions with phenacylhalogenides and analogues (entry 1) is by far the best method. Synthesis of altogether more than 150 derivatives are described in... 

Table 4 Synthesis of [1,2,4]triazolo[3,4-b]thiadiazines by reaction of 3-mercapto-4-amino[1,2,4]triazoles with a-halo-oxo reagent...

Mercaptotriazoles 133, available from thiosemicarbazones, are versatile starting materials for the preparation of thiazolo[3,2-h][l,2,4]triazoles. Treatment with a-halo ketones (and esters) yields S-alkylated derivatives that are cyclized to 134 either directly or on treatment with acidic catalysts (e.g., P2O5/H3PO4). 

Many triazole derivatives are accessible by exchange of 3- or 5- halo, hydroxy, alkoxy, aryloxy, alkylthio, amino, or cyano groups <67EGP59288, 69BRP1157256, 70KGS1701,75BSF1649). A kinetic comparison of haloazole reactivities has been reported <67JCS(B)64l). 

Rearrangement of acyl and halo groups are the most common reactions of nitrogen substituents of triazoles. 

Triazoles are brominated at the 4- or 5-positions, but only if there is no A-substituent (74AHC( 16)33). This also applies to 1,2,4-triazoles. A-Halo derivatives are frequently isolated as intermediates (81HC(37)289). 

Halo-l-methyl-l,2,3-triazoles undergo substitution reactions with amines, but the 4-halo analogues do not. 5-Chloro-1,4,-diphenyl-1,2,3-triazole with sodium cyanide in DMSO gives the cyano derivative (63JCS2032). 1-Substituted 3-chloro- and 5-chloro-l,2,4-triazoles both react with amines. 

The ketone 64 still has a 1,2-diX relationship but at the carbonyl oxidation level, so we disconnect to another molecule of triazole 62 and the a-halo ketone 66 is easily made by a Friedel-Crafts reaction using available chloroacetyl chloride. This time we buy the 1,2-diX relationship in the form of chloroacetyl chloride. 

Triazole pesticides are made by reaction between 1.2.4 triazole and a halo-compound... 

Reaction of 5-halo-l,2,3-thiadiazoles with 1,3-diaminopropane leads to bis(l,2,3-triazolyl-l,2,3-thiadiazolyl)sulfide 105. Further intramolecular cyclization affords bis-[l,2,3]triazolo[l,3,7]thiadiazocine ring system 106 in 79% yield (Scheme 25 <20030BG4030>). The role of the ester groups on both the 1,2,3-triazole and 1,2,3-thiadiazole rings in the formation of the final product is essential. 

In a one-pot reaction, a,a-disubstituted a-halo carbonyl compounds 1 (R, potassium thiocyanate, acetic acid, and monosubstituted hydrazines 3 are transformed into dihydro-lfT-imidazo[l,5- 7][l,2,4]triazole-2,5 (3H,6H)dithiones 8 (Scheme 1) (93TH, 01TH). With R =H, the reaction takes a different course (cf. Section 2.3). 

Scheme 1 One-pot synthesis of lmldazo[l,5-b][l,2,4]triazoles 8 from of a,a-dlsubstltuted a-halo carbonyl compounds 1 with potassium thiocyanate in acetic acid and monosubstituted hydrazines 3.

Halogeno-1,2,4-triazoles are reductively dehalogenated with red phosphorus and hydriodic acid (05la(343)i) but, unlike A/ halo compounds, not by bisulfite (67zci84). 

Rearrangement of acyl and halo groups are the most common reactions of triazoles with functions on nitrogen. The chemistry of 4-hydroxytriazoles , in effect Af-oxides, has been less extensively studied than that of triazolinones. The N—O bond is cleaved by phosphorus halides and acidic anhydride but not by oxidation with permanganate or by alkaline bromination (70jpr610). 

Conversion of existing functions include the oxidation of aliphatic or aromatic side-chains, one of the earliest preparative techniques of triazole chemistry. Hydrolysis of cyanides obtained by displacement of halo, nitro and diazo groups is of comparable importance. 

The applicability of cyanation has been successfully demonstrated in several instances. Thus, a 2 -phosphonylated 3 -trifluoromethylsulfonyhiucleoside reacts smoothly with w-Bi Nf N in MeCN to give the cyanation product in 45% yield (Scheme 6.36). With halo derivatives, assistance is needed, and 3-bromo-3-(l-trityl-l,2,4-triazol-3-yl)propylphosphonate reacts with NaCN and 15-crown-5 in DMF at room temperature,2 295 whereas diethyl 4-(bromomethyl)benzylphosphonate reacts with KCN and Nal in AcjO/HgO.- The preparation of (3-cyanaziridiii-2-yl)methylphospho-nates by addition of McjSiCN to (2H-azirin-2-yl)metliylphosphonates has also been reported. ... 

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