Regiospecific Synthesis of 1,2-Bis(azolyl)ethanes

Este trabalho mostra a síntese de 1,2-bis-(5’-trialometilisoxazol-3’-il)etanos (3-6) e 1,2-bis(5’trialometilpirazol-3’-il)etanos (7-10) a partir da ciclocondensação de 1,1,1,10,10,10-hexahalo-4,7dimetoxideca-3,7-dien-2,9-dionas (1 e 2) com hidroxilamina e hidrazinas. Também é mostrada a síntese dos 1,2-bis(5’-alcoxicarbonilpirazol-3’-il)etanos (11-14) via reação da dienona 2, triclorometilsubstituída, e hidrazina.


Introduction
Most organic compounds belong to the heterocyclic class and a great number of heterocycles have been of significant help for the human beings.Isoxazoles and pyrazoles belong to this class of compounds and are known to be important intermediates for the preparation of agrochemicals and pharmaceutical compounds. 1,2The 1,2bis(azolyl)ethanes consist of two N-donor units linked by a flexible spacer.These compounds show desirable characteristics to be used as ligands of metals because they can either bridge two different metal ions, or act as bidentate chelants of single metal ions. 35][6][7] These compounds are of general interest as precursors for a variety of halomethyl-substituted heterocyclic compounds, e.g.isoxazoles, 8,9 pyrazoles, 10-12 pyrimidines 13,14 and diazepines. 15
On the other hand, the reaction of 2 with two equivalents of hydrazines in a mixture of pyridine and methanol (or ethanol) under reflux for 24 hours led to 5alkoxycarbonyl pyrazoles 11-14 (Scheme 2, Table 2).This reaction condition promoted the cyclocondensation and the hydrolysis of the trichloromethyl group. 18,19In addition, the treatment of 5-trichloromethylpyrazoles 8 and 10 in pyridine with an appropriate alcohol under reflux, also led to the carboxypyrazoles 11-14, in good yields (Scheme 2, Table 2).
The structure of pyrazoles 7 -15 was assigned by their NMR spectra.The 1 H NMR spectrum of aromatic pyrazoles displays the signal for methylene-3' at δ 3.19 -3.85, for the aromatic H-4' at δ 6.33 -6.85 and for 15 the N-Me appeared at δ 2.97.In the 13 C NMR spectra of 7-15 the signal from C-3' appeared at δ 138.7 -155.3 and signal from C-5' at δ 140.3 -145.0.For the pyrazole 15 they were assigned with two-dimensional correlation spectra HMBC (Heteronuclear Multiple Bond Correlation) by observing a cross peak between the C-5' (142.5 ppm) and the N-methyl hydrogen signal at 3.85 ppm that confirms the 5-ethoxycarbonylpyrazole isomers.The signals for C-4' of the pyrazole ring for compounds 7-15 appeared around δ 102.6 -111 (Table 3).
pyrrolo [1,5-b]pyrazole 16 (Scheme 3).The product was characterized by 1 H, 13 C NMR and 2D HMQC and HMBC spectroscopy data (Table 3).The presence of two CCl 3 groups with different chemical shift and the absence of methoxy group agree with the structure.To our knowledge there are no reports in the literature of this condensed heterocyclic compound.The formation of this condensed product was not observed when precursor 1 was used under the same conditions.

Conclusion
In conclusion, compounds 1 and 2 demonstrated high versatility as building blocks for the synthesis of many types of heterocycles that could provide potential biological activity.In addition, the use of 1,2-bis(5'-trihalo-methylpyrazol-3'-yl)ethane (7 and 9) as ligands in coordination chemistry, is under investigation. 20Also, a new type of condensed heterocycle (16) has been synthesized.

Experimental
Unless otherwise indicated, all common reagents and solvents were used as obtained from commercial suppliers without further purification.Yields listed in Table 1 and 2 are for isolated compounds. 1H, 13 C NMR spectra were recorded on a Bruker DPX 400 spectrometer ( 1 H at 400.13 MHz and 13 C at 100.63 MHz) at 298 K, digital resolution of ±0.01 ppm, 0.5 mol L -1 in CDCl 3 , Acetone-d 6 or DMSOd 6 containing TMS as in internal standard.All spectra were acquired in a 5 mm tube, at natural abundance.Mass spectra were registered in a HP 5973 MSD spectrometer connected to a HP 6890 GC and interfaced by a Pentium PC.The GC was equipped with a split-splitless, injector, auto sampler, cross-linked HP-5 capillary column (30 m, 0.32 mm of internal diameter), and helium was used as the carrier gas.

Table 1 .
Reaction conditions, a yields and melting points of alkoxycarbonyl pyrazoles 3-10 See experimental part; b The melting points are uncorrected; c Yields of isolated compounds. a

Table 2 .
Reaction conditions, a yields and melting point of pyrazole compounds 11-15 a See experimental part; b The melting points are uncorrected; c Yields of isolated compounds.

Table 3 .
Spectral data a of compounds 3-16 a NMR spectra were recorded on a Bruker DPX 400 in CDCl 3 /TMS; b aceton-d 6 ; c DMSO-d.