Solvent-free reactions triazoles

The examples in Table 9.1 demonstrate scale-up by two orders of magnitude for solvent-free reactions. Hundreds of grams of product were obtained on the larger scale, with little difference in the final percentage yield or reaction conditions. The phenyla-cylation of 1,2,4-triazole (entry 2) was not only amenable to scale-up by a factor of 90, but enhanced selectivity to the N — 1 product occurred under microwave irradiation. Classical heating affords a mixture of N — 1 and N — 4 alkylated products as well as quaternary salts80. 

A [3+2] cycloaddition/elimination procedure to 1//-1,2,3-triazoles involves the solvent-free reaction of trimethylsilylazide with nitroethenes 50 in the presence of TBAF... 

Triazoles have been obtained via microwave-assisted [3-i-2] cycloaddition, under solvent-free conditions [54], starting from organic azides and acetylenic amides at 55 °C for 30 min (Scheme 23). The complete conversion of the reagents into AT-substituted-1,2,3-triazoles 69 was achieved without decomposition and side products. A control reaction carried out at the same temperature in an oil bath did not give the cycHc products, not even after 24 h of reaction time. 

Triazole derivatives are very interesting compounds that can be prepared by 1,3-dipolar cycloadditions between azides and alkynes. Loupy and Palacios reported that electron-deficient acetylenes react with azidoethylphosphonate 209 to form the regioisomeric substituted 1,2,3-triazoles 210 and 211 under microwaves in solvent-free conditions (Scheme 9.65) [114]. This procedure avoids the harsh reaction conditions associated with thermal cycloadditions (toluene under reflux) and the very long reaction times. 

The 1,3-dipolar cycloaddition of azides to acetylenic amides is particularly difficult under conventional thermal conditions and extended reaction times of 14 h to 1 week have been reported32,33. Katritzky reported a microwave-mediated solvent-free variant ofthis procedure to give N-substituted C-carbamoyl- 1,2,3-triazoles in good to excellent yields in only 30 min (Scheme 3.19)34. 

Triazoles are generally prepared by the 1,3-dipolar cycloaddition of an alkyne with an azide at elevated temperatures. Thus, reaction of organic azides with acetylenic amides was significant only after 12 h refluxing in toluene. As a contrast, microwave dielectric heating at 55-85 °C under solvent-free conditions furnished the corresponding disubstituted... 

Direct alkylation with classical heating gave a mixture of 1- and 4-alkylated triazoles together with quaternary salts resulting from alkylations at both the 1 and 4 positions. Interestingly, it has been shown that benzylation and phenacylation occurred selectively at position 1 without any base under the action of irradiation and under solvent-free conditions (Scheme 10.94) [183]. The reaction with (2,4-dichloro)phenacyl chloride was studied in particular depth (Chapter 4). This reaction has been scaled-up to more than 100 g by use of a Synthewave 1000 oven. 

An interesting report from Loupy et al. described the use of solvent-free conditions and microwaves for the synthesis of regioisomeric 1,2,3-triazoles 188 and 189 with substantial reduction for reaction times - down to 5-30 min compared with 30-40 h under reflux in toluene under thermal conditions for the 1,3-dipolar cycloaddition between phosphonate azides 186 and acetylenic esters 187 (Scheme 11.48) [31c]. 

Mukheijee N, Ahammed S, Bhadraa S, Ranu BC. Solvent-free one-pot synthesis of 1,2,3-triazole derivatives by the Click reaction of alkyl halides or aryl boronic acids, sodium azide and terminal aUcynes over a C11/AI2O3 surface under ball-milling. Green Chem 2013 15 389-97. 

Coffinier et al have developed solvent-free, two step, three-component (acyl chloride, isocyanide and phosphite) synthesis involving Nef and Perkov reactions via the intermediate (59), leading to keteneimines which might easily be converted to O-phosphorylated tetrazoles and triazoles (Scheme 11). 

Chiral pyrrolidine-triazole 91 (10 mol%), obtained by click chemistry , was used as catalyst in combination with TFA (1.5 mol%) in the aldol reaction between cyclohexanone (10 equiv.) and several aldehydes under solvent-free conditions at 0°C, affording the aldol products in good yields and diastereoselectivities (86-93% yield, 84-92% de) albeit with low enantioselectivities (23-28% ee) [161]. 

Hosny et al. investigated the synthesis of new series of quinolinyl-mercapto-triazoles exhibiting high antitumor activity against the breast cancer cells the triazoles were prepared from the corresponding coumarins by condensation with thiosemicarbazide. The target coumarins were efficiently synthesized by Pechmaim reaction between substituted phenols and ethyl acetoacetate catalyzed by montmorillonite K-10 xmder solvent-free conditions [67]. 

Similar 1,3-dipolar cycloadditions of azides and alkynes produce thermally stable, aromatic triazoles. Ma et al. prepared triazole 212 by pressure-accelerated cycloaddition of azide and alkyne in the crystalline state (present as salt 211) at room temperature (Scheme 51) [79]. Standard reaction conditions requires the use of copper catalyst. An analogous result was previously obtained by solvent-free pressurization (10 kbar, 2-4 h, RT) of aryl azides and tri-methylsilylacetylene by Zanirato and co-workers [79]. 

A homogeneous Ag(I)-catalyst (65) has been developed for the 3 -I- 2-cycloaddition reaction of azides to terminal alkynes to form the corresponding 1,4-triazoles. A simple metal-free synthesis of pentafluoroalkylated 1,2,3-triazoles has been developed from the 1,3-dipolar cycloaddition reaction of azides with methyl 2-perfluoroalkynoates. Again, the intramolecular alkyne-azide Huisgen 3 -I- 2-cycloaddition reaction in water is an example of Click reaction in the absence of a metal catalyst. The Cu(I)-catalysed azide-alkyne 3-1-2-cycloaddition reaction yielded 1,4-disubstimted 1,2,3-triazoles in excellent yields in 2-25 min under solvent-free conditions. The use of 16-electron... 

Garrigues et al. (1996) reported the microwave-assisted Diels-Alder reaction between anthracene and azadienes supported on graphite, while Diaz-Ortiz et al. (2000) studied the solvent-free microwave-assisted Diels-Alder cycloaddition reaction, where a 1,2,3-triazole ring serve as a diene towards DMAD. 

Regarding the aNHC hgands, the l,3-bis(2,6-diisopropylphenyl)-2,4-diphenyhmidazohum salt, as a aNHC ligand, forms a copper(I) chloro complex, which efficiently catalyzes reactions of azides, even those sterically hindered, with both terminal and internal alkynes, to give 1,4-substituted 1,2,3-triazoles in excellent yields at room temperature within short reaction time under solvent-free conditions with a loading of 0.005 mol% [30]. 

N-Heterocyclic carbenes are an example of a family of nucleophilic catalysts [84-87]. For instance, the polymerization of p-butyrolactone was catalyzed by l,3,4-triphenyl-4,5-dihydro-l//,l,2-triazol-5-ylidene in the presence of methanol as an initiator [86]. This reaction was carried out in toluene at 80 °C. Nevertheless, an undesired elimination (Fig. 4) reaction was observed and control of the polymerization was lost. This issue was overcome by using ferf-butanol as a co-solvent, which reacts reversibly with the free carbene to form a new adduct. Owing to the decrease in the concentration of the free carbene, the elimination is disfavored and the polymerization is then under control provided that a degree of polymerization below 200 is targeted. As a rule, the reactivity of N-heterocyclic carbenes depends on their substituents. Hindered N-heterocyclic carbenes turned out to be not nucleophilic enough for the ROP of sCL. Recently, it was shown that unencumbered N-heterocyclic carbenes were more efficient catalysts [87]. 

Bromination is usually performed with bromine in a suitable solvent, but in a few cases where this is ineffective (e.g., 415197b and 414143b), N-bromosuccinimide has been employed. In the case of 414, bromination was found to be successful only when R1 = Me. Chlorination of 410 has been achieved with sulfuryl chloride (Table III). Thiocyanations have been carried out either with bromine and ammonium thiocyanate307 or bromine and thiourea236,242,414 though the structures of the products (thiocyanates or isothiocyanates) have not been established with certainty. Kano242 showed that imidazo[2,1-6]-1,3,4-thiadiazole 411 undergoes bromination and thiocyanation preferentially at C-5 (position a, Scheme 18) when this position is free. C-5-substituted derivatives are brominated at C-6 (position b), but thiocyanation fails. Electrophilic substitution reactions in 1 //-pyrrolol 1,2-6]-s-triazole have also been studied.289 ... 

Earlier, reference was made to the potential third mechanism associated with nucleophilic displacements at phosphoryl phosphorus, namely that which might involve the participation of a phosphaacylium cation. Mixed sulphonic-phosphonic or sulphonic-phosphinic anhydrides 645 (Z = O, R = Me or 4-methylphenyl) have been obtained from the free phosphorus(V) acid and the 1,2,4-triazole 646 in the presence of trifluoromethanesulphonic acid, or 645 (Z = O, R = CF3) from the imidazolides 647 and trifluoromethanesulphonic acid and / r/-butylphenylphosphinothioic acid with trifluoromethanesulphonic anhydride yield the mixed 0-anhydride 648 (R = CF3), some reactions of which are illustrated in Scheme 76 ". Of those reactions, the formation of the iodide 649, albeit in low yield when the reaction is carried out in MeOH, with stereochemical retention of configuration at phosphorus, contrasts with the inversion of configuration observed for the remainder, and which is normally encountered for Sn2(P) displacements. The reaction of648 with methoxybenzene to yield the phosphine sulphide 650 in a solvent of high ionizing power (1,1,1,3,3,3-hexafluoropropan-2-ol a lower yield was obtained in a... 

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