Lewis acid-catalyzed Wolff cyclocondensation in the synthesis of (1 H -1,2,3-triazolyl)furoxans

Novel regioselective approach to the synthesis of (1 H -1,2,3-triazol-1-yl)furoxans based on Lewis acid-catalyzed Wolff cyclocondensation of aminofuroxans with diazo-β -dicarbonyl compounds has been developed. This approach allows to involve aminofuroxans as substrates which are very weak nucleophiles and usually do not participate in reactions with common electrophiles.


Introduction
One of the useful tools for the design of new drug candidates with improved pharmacokinetic profiles is the molecular hybridization of different compounds with known pharmacological activity. 1,2To solve this issue, it is necessary to create new, highly effective and regioselective methods.Recent scientific investigations of our laboratory were directed towards the synthesis and reactivity of nitrogen-oxygen containing heterocycles -1,2,5-oxadiazole 2-oxides (furoxans). 3,4Furoxans are unique representatives of heterocyclic compounds.][22][23][24][25][26][27][28] Among synthesized compounds (1,2,3-triazol-1-yl)furoxan derivatives 1 attract special attention due to a wide variety of their pharmacological activity.The 1,2,3-triazole nucleus is found in a large number of compounds with agrochemical and pharmaceutical uses, 29 shows anti-HIV, 30 antimicrobial, 31 antibacterial, 32 and antitumor 33 properties and has also found many applications in chemical industries. 34Cycloadditions of azides to alkynes and their derivatives (Huisgen reaction) [34][35][36] continue to be the main synthetic route to 1,2,3triazoles.The reactions are usually catalyzed with transition metals and carried out at room or elevated temperature.Reactivity and regioselectivity in reactions of acetylenes with azides depends strongly on electronic and steric factors of both reagents.
Earlier 22 we attempted to synthesize (1,2,3-triazol-1-yl)furoxans 1 based on the [3+2] cycloaddition of azidofuroxans with acetylene derivatives.Unfortunately, in contrast to analogous reactions of other heterocyclic azides (in particular, azidofurazans 37,38 ), the expected cycloaddition products were not obtained in any of the organic solvents even at prolonged heating.The [3+2] cycloaddition of azidofuroxans to internal and terminal acetylenes was found to occur only in the ionic liquids medium at prolonged heating and resulted in (1H-1,2,3-triazol-1-yl)furoxans in moderate to good yields.The reaction with terminal acetylenes proceeded with high regioselectivity, but another regioisomer was also formed in significant amounts.A decreased reactivity of azidofuroxans in [3+2] cycloaddition reaction connected, evidently, with a strong electronwithdrawing character of the furoxan ring. 39Therefore, it was of interest to develop a new, more effective and regioselective method for the synthesis of (1H-1,2,3-triazol-1-yl)furoxans 1.
We paid attention to 1,2,3-triazole synthesis based on Wolff's cyclocondensation of diazoketones with aromatic and aliphatic amines under different catalysts.This reaction was discovered in 1902 40,41 and has become one of the known synthetic approaches to 1,2,3-triazoles. 42,43The advantage of this method is that it yields only one of the two possible regioisomers of the 1,2,3-triazoles with unsymmetrically substituted substrates and safe amines are used instead of dangerous azido derivatives.Since aminofuroxans are rather available compounds, 3 we aimed to develop new, regioselective method for the synthesis of (1H-1,2,3-triazol-1-yl)furoxans 1 by an interaction of 4-aminofuroxans 2 with diazo-β-dicarbonyl compounds 3.

Results and Discussion
The investigations were begun with screening of the optimal conditions for the reaction of aminofuroxan 2a with 3-diazo-2,4-dioxopentane (3a) (Table 1).Different Lewis acids as catalysts, their amount, temperature, solvent and reactants ratio were varied.As expected, in absence of any catalyst the reaction did not occur (Table 1, entry 1).With the use of 10 mol.% of BF3•OEt2 target (1,2,3-triazolyl)furoxan 1a was isolated in moderate yield (entry 2).The increase of catalyst amount to 20 mol.% significantly increased the yield to 83% (entry 3), while further increase of catalyst molar equivalents resulted in yield decrease (entries 4,5).Probably, 10 mol.% of BF3•OEt2 is insufficient, while the increase in amount of catalyst more than 20 mol.% partially blocks the amino group of furoxan 2a.Utilization of transition metal salts afforded target product only in trace amounts (entries 6-9).Replacement of MeCN with DMF or [bmim]BF4 as well as variation of temperature and reactants ratio also did not improve the product's yield (entries 10-15).Iron (III) chloride and nickel nitrate were also ineffective in this reaction (entries 16,17).Therefore, the optimal conditions were found to include reactants ratio 1:1 and 20 mol.% BF3•OEt2 as catalyst in MeCN at room temperature.This approach to the (1H-1,2,3-triazol-1-yl)furoxan scaffold assembly encouraged us to examine the substrate scope of the reaction of aminofuroxans 2 with diazo-β-dicarbonyl compounds 3. The reaction of aminofuroxans 2a-d incorporating phenyl, methyl, ester and acetyl groups respectively proceeded successfully with 3-diazo-2,4-dioxopentane (3a), however, the highest yield of final 1,2,3-triazole was obtained for compound 1a.Among diazo compounds, 2-diazoacetoacetic ester (3b) was found to be less reactive since the yields of final products 1b,d,f were lower in comparison with the yields of compounds 1a,c,e.Moreover, the reaction of aminofuroxan 2d comprising acetyl group at C(3) atom of the furoxan ring with diazo compound 3b did not occur.In general, the yields of (1H-1,2,3-triazol-1-yl)furoxans were moderate which is explained by low basicity and low nucleophilicity of aminofuroxans due to the strong electron-withdrawing effect of the furoxan ring. 39Interestingly, the reaction of 3-amino-4-phenylfuroxan, which is more nucleophilic than the corresponding 4-amino isomer 2a, with diazo compound 3a did not occur due to the decomposition of starting materials.
Table 2. Substrate scope for the reaction of aminofuroxans 2 with diazo compounds 3 a a Isolated yields are for an average of two runs.b 1.5 equiv. of 3a were used.
A plausible mechanism for the BF3•OEt2-catalyzed reaction of aminofuroxans 2 with diazo compounds 3 is outlined in Scheme 1.Since aminofuroxans are of very low basicity and correspond to weak nucleophiles 39 it seems that BF3•OEt2 activates the diazo compound 3 to generate complex 4. The electrophilicity of the carbonyl group in intermediate 4 has increased enough for the condensation with aminofuroxan 2 to occur.Finally, the intramolecular cyclization in imine 5 completes the regioselective 1,2,3-triazole 1 formation incorporating R 2 substituent at C(5) atom of the triazole ring.

Conclusions
In summary, atom-economical approach to the synthesis of (1H-1,2,3-triazol-1-yl)furoxans based on BF3•OEt2catalyzed Wolff cyclocondensation of aminofuroxans with diazo compounds has been developed.The advantages of this method are operational simplicity, step economy and the use of readily accessible reagents.It was estimated that the reaction is quite sensitive to the nature of the substituent either at furoxan ring or in diazo derivative.Capability to participate in Wolff cyclocondensation decreases with an increase of the electron-withdrawing character of the functional groups in both substrates.

Experimental Section
General.All reactions were carried out in well-cleaned oven-dried glassware with magnetic stirring. 1H and 13 C NMR spectra were recorded on a Bruker AM-300 (300.13 and 75.47 MHz, respectively) spectrometer and referenced to residual solvent peak.The chemical shifts are reported in ppm (δ); multiplicities are indicated by s (singlet), d (doublet), t (triplet), qv (quartet), m (multiplet) and br (broad).Coupling constants, J, are reported in Hertz.The IR spectra were recorded on a Bruker "Alpha" spectrometer in the range 400-4000 cm -1 (resolution 2 cm -1 ).Elemental analyses were performed by the CHN Analyzer Perkin-Elmer 2400.The melting points were determined on "Stuart SMP20" melting point apparatus and are uncorrected.Analytical thin-layer chromatography (TLC) was carried out on Merck 25 TLC silica gel 60 F254 aluminum sheets.The visualization of the TLC plates was accomplished with a UV light.Column chromatography was performed on silica gel 60 A (0.060-0.200 mm, Acros Organics).All solvents were purified and dried using standard methods prior to use.4-Amino-3-phenylfuroxan 2a, 45 4-amino-3-methylfuroxan 2b, 46 4-amino-3-(methoxycarbonyl)furoxan 2c, 47 3acetyl-4-aminofuroxan 2d 48 and diazo compounds 3a,b 41 were synthesized according literature.All other reagents were purchased from Acros Organics and used without further purification.

a
Isolated yields are for an average of two runs.b Determined by 1 H NMR spectroscopy.c Decomposition of initial compounds was observed.

Figure 1 .
Figure 1.A general view of the 1a molecule.Non-hydrogen atoms are represented by probability ellipsoids of atomic vibrations (p = 50%).

Figure 2 .
Figure 2. The fragment of piles in the crystal of 1a (a) and the fragment of a layer (b).