Transition-Metal-Free Catalytic Synthesis of 1,5-Diaryl-1,2,3-triazoles

Abstract

Abstract1,5-Diarylsubstituted 1,2,3-triazoles are formed in high yield from aryl azides and terminal alkynes in DMSO in the presence of catalytic tetraalkyl ammonium hydroxide. The reaction is experimentally simple, does not require a transition-metal catalyst, and is not sensitive to atmospheric oxygen and moisture.The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) is a reliable means for the synthesis of 1,4-disubstituted-1H-1,2,3-triazoles. 1 The exceptional stability of 1,2,3-triazoles and the availability of a reliable synthesis leading to these heterocycles have enabled widespread applications of this previously underutilized class of azoles in medicinal chemistry, chemical biology and materials science. 2 In contrast to the 1,4-disubstituted-1H-1,2,3-triazoles, general and regioselective routes leading to the 1,5-regioisomers are not as well developed. [3][4][5][6][7][8] Although syntheses relying on the nucleophilic attack by the acetylide at the electrophilic terminal nitrogen of the azide are known, 9 the requirement for the stoichiometric lithium or magnesium acetylide reagent imposes obvious limitations on the range of functional groups that are compatible with these processes. Reported here is a mild and experimentally simple catalytic method for the generation of the reactive acetylides which readily react with organic azides resulting in the exclusive formation of 1,5-disubstituted triazoles.We envisioned that the high acidity of aryl acetylenes in dimethylsulfoxide [10][11][12] should allow formation of the reactive acetylide species by treatment of the alkyne with a hydroxide or fokin@scripps.edu. Supporting Information Available. Experimental procedures, characterization data, copies of 1 H NMR and 13 C NMR spectra. This material is available free of charge on the Internet at http://pubs.acs.org. alkoxide base in this solvent. In fact, formation of acetylide intermediates has been proposed by Ishikawa and co-workers in their studies of the alkynylation of ketones. 13 Screening of various hydroxides and alkoxides confirmed this hypothesis, revealing that anhydrous sodium, potassium, cesium hydroxides, and aqueous tetramethylammonium and benzyltrimethylammonium hydroxides catalyze formation of 1,5-diarylsubstituted-1H-1,2,3-triazoles in DMSO at room temperature (Table 1). NIH Public AccessDry DMSO and less nucleophilic bases such as potassium tert-butoxide can also be used to minimize hydrolysis of substrates which contain base-sensitive functionalities. In many cases, the desired products precipitated upon addition of 5-20× volume of ice-cold water and were isolated by simple filtration. Reactions in DMSO afforded higher isolated yield than in DMF on larger scale and at higher concentration. Although tetraalkylammonium hydroxides resulted in the slightly diminished yield of the product compared to powdered KOH, the shorter reaction time and the experimental convenience of using aqueous base solutions make tetraalkylammonium hydroxides advantageous catalysts for practical reasons.While o...

7-Aryl-triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrase IX and XII

“…The proper aniline (0.5 g, 1.0eq) was dissolved in a 4 M HCl aqueous solution (5 ml) at 0 C. NaNO 2 (1.2 eq) was slowly added and the resulting solution was stirred at the same temperature for 0.5 h. Then NaN 3 (1.5 eq) was added portion-wise and the mixture was stirred at r.t. for 0.5 h. The reaction mixture was filtered off or extracted with Et 2 O (2 Â 15 ml) and the combined organic layers were dried over Na 2 SO 4 , filtered off and the solvent evaporated in vacuo to afford the corresponding phenylazide which was used without further purification. Experimental in agreement with reported data 46 . Experimental in agreement with reported data 47 .…”

Synthesis and Antimicrobial Activity of Pyrazolyl Triazoles

“…as KBr pellets and the wave numbers were mentioned in cm -1 . The 1 H and 13 C NMR spectra were recorded in DMSO-d 6 on a Bruker-400 spectrometer operating at 400 and 100 MHz, respectively. The chemical shifts are reported in δ (ppm) using TMS as an internal standard.…”

“…In addition to this signals corresponding to pyrrole ring protons appeared at downfield region, C 3 -H at 6.03, C 4 -H at 6.20 and C 5 -H at 6.98 ppm which confirmed the extended conjugation. All the new compounds are further characterized by IR, 13 C NMR, mass and elemental analysis.…”

“…On the other hand, 1,3-dipolar cycloaddition of azides with alkynes under thermal conditions, in the presence of copper or ruthenium catalysts resulted in 1,2,3-triazoles [10][11][12]. Transition-metal-free synthesis of 1,2,3-triazoles was reported by the cyclocondensation of organic azides with terminal alkynes in the presence of a catalytic amount of tetramethylammonium hydroxide [13].…”

Szteránvázas azidok előállítása és réz(I)-katalizált dipoláris cikloaddíciói

“…Fokin és munkatársai átmenetifém alkalmazása nélkül, tetraalkilammónium-hidroxid katalizátor segítségével, enyhe körülmények között állítottak elő különböző 1,5-diarilszubsztituált-1,2,3-triazolokat (10. ábra) [74]. Az 1980-as évek elején Klaubert és munkatársai számoltak be arról, hogy 130 °C-on történő hevítéssel állítottak elő tetrazolokat 60% körüli hozammal, kiindulási anyagként benzil-azid származékokat és alkil-cianoformátokat alkalmazva [77].…”