Synthesis of substituted 1,2,3-triazoles via N -sulfonylaziridines

Nucleophilic ring-opening of N -sulfonylaziridines by sodium azide leads to β -azidoamines. The regioselectivity of this reaction and new efficient catalyst for such 1,3-dipolar cycloaddition are reported. Several 1,2,3-triazoles have been synthesized and their structures established by X-ray crystallography, MS, IR and 1 H NMR spectral data.


Introduction
N-Substituted aziridines are versatile intermediates for the synthesis of many biologically active compounds that are valuable for new drugs development.There is a growing interest in ring opening reactions of aziridines with various nucleophiles due to their high reactivity and ease of preparation 1 .N-Sulfonyl aziridines are well-known alkylating agents and they are used for the synthesis of several types of heterocyclic compounds [2][3][4][5] .
Antibacterial, antifungal, antiviral, anti-inflammatory and analgesic properties of 1,2,3triazoles have been extensively studied.Recently some new 1,2,3-triazole derivatives have been reported as inhibiting tumor proliferation, invasion, and metastasis. 6e now report a new method for the synthesis of 1,2,3-triazole derivatives containing aminoethyl groups from N-sulfonylaziridines. The process can be carried out stepwise, or as multicomponent ("one-pot") synthesis.Nucleophilic ring-opening of aziridines by sodium azide was studied as a synthetic route to the substituted β-azidoamines.3] However, we have established that azidolysis can be performed without catalyst in DMF in the presence of weak acids, that allowed us to develop a one-pot synthesis of 1,2,3triazoles 3 by the reaction of aziridines 1 with NaN 3 , acetylenes and catalytic amounts of Cu 2 Cl 2 in aqueous acetonitrile under reflux for 2-3 h in good to excellent yields.

Results and Discussion
We started this work by studying an aziridine ring-opening with NaN 3 in aqueous DMF (DMF:H 2 O -10:1) at room temperature.The reaction (Scheme 1) appeared to be pH dependent.To obtain desired product an addition of acid precursor was necessary, however strongly acidic conditions caused formation of hydrazoic acid, lowering yield of the product 3.

Scheme 1
It was found that bubbling carbon dioxide through the reaction mixture kept pH at the optimum level.Reaction was completed when the pH did not change during several minutes.The acidity of the system (CO 2 +H 2 O) was enough to form anion 2, but not for the generation of HN 3 from sodium azide (K α HN 3 = 2,0*10 -5 , K α CO 2 +H 2 O = 4,45*10 -7 ).Precipitation of NaHCO 3 was observed during the reaction.
The ring-opening of N-arylsulfonylaziridines derived from styrene and indene 1a-c, 1g occurred in a regioselective manner with preferential attack at the benzylic position.In contrast, alkyl-N-arylsulfonylaziridines, gave 1h-i predominantly resulting from terminal attack by azide.
The reaction of cyclohexyl-N-arylsulfonylaziridines 1d-f with NaN 3 provided the desired trans-isomer as a single isomer.Relative stereochemistry was established by 1 NMR.This conclusion is also supported by X-ray analysis (Figure 1).
The β-azidoamines obtained are white crystalline products or colorless liquids.They may be used as precursors to 1,2,3-triazoles without further purification.
Our next step was to study 1,2,3-triazole formation by cycloaddition of intermediates 3 to mono-and di-substituted alkynes.It was found that reaction of alkyl azides 3 with phenylacetylene proceeds efficiently under reflux in toluene in the presence of catalytic amounts of Cu 2 Cl 2 in 15-30 min.Reaction takes 10-20 h without catalyst.Presumably terminal alkynes form a complex with Cu(I) and therefore the reactivity of substrates increases.Usually, precipitation of crude 1,2,3-triazoles, contaminated with copper salts was observed.In order to separate 1,2,3-triazole from Cu(I), H 2 S gas was bubbled into the DMF solution.Copper sulfide was removed by filtration.Final product was obtained after subsequent dilution with cold water and filtration.
Dimethyl acetylenedicarboxylate also reacted with alkyl azides to produce substituted 1,2,3triazoles.However, in this case catalysis by Cu(I) was not observed possibly because of the absence of a terminal hydrogen atom in the acetylene, which makes complex formation impossible.Products of type 5 were also observed but required a long reaction time to form.

Scheme 2
We modified the reported two-step sequence, i.e. aziridine ring-opening followed by a cycloaddition, to provide a "one-pot" synthesis of 1,2,3-triazoles 4, 5.This was successfully achieved by using N-sulfonylaziridines, NaN 3 , phenylacetylene and catalytic amounts of Cu 2 Cl 2 in aqueous acetonitrile (Scheme 3).The advantage of this method is that it produces substantial amounts of 1,2,3-triazoles in a short time, avoiding purification of the intermediated azides.The use of a "one-pot" method did not decrease yield of the 1,2,3-triazoles 4 (Table 2).

General procedure of nucleophilic ring opening of N-sulfonylaziridines with sodium azide
To a solution of N-sulfonylaziridine (0.02 mol) in DMF (50 mL) was added sodium azide (0.022 mol) and water (10 mL).After dissolving the sodium azide, carbon dioxide was bubbled into mixture.The reaction was completed when pH of the solution became constant.The reaction mixture was diluted with cold water and the product was extracted with ethyl acetate (3 x 50 mL).The extracts were separated, dried over sodium sulfate and solvent removed under vacuum to give (3b-f) either as white crystals or a colorless liquid.General procedure of synthesis of 1,2,3-triazoles (4, 5) А.Using β-azidoamines.To a solution of β-azidoamines (0.01 mol) in 40 mL of toluene was added phenylacetylene (0.011 mol) and catalytic amount of Cu 2 Cl 2 .The resulting mixture was refluxed for 30 min.Then triazole contaminated with copper sulfide was filtered off and subsequently purified by bubbling of H 2 S through the solution in DMF.The filtrate was cooled down and the precipitate was filtrated to give pure triazole.

Table 2 .
Continued a Yields in parenthesis are given for "one-pot" synthesis of 4 and 5 from 1 as described in the Experimental Section. 3 solution on an Impact 400 ("NICOLET") spectrometer.Melting points were taken in open capillary tubes and are uncorrected.The single-crystal X-ray study was performed on a Siemens P3/PC diffractometer.Compound 4e, (C 20 H 22 N 4