Synthesis of 1,1 ′ -methylenebis(1,2,4-triazole) functionalized in the methylene bridge. A new approach to dendrons bearing heterocyclic rings on the periphery

3,3-Bis(1,2,4-triazol-1-yl)-1-propanol was obtained by reduction of its methyl carboxylate derivative. This compound is able to form the first generation dendron containing two bis(1,2,4-triazol-1-yl)methyl systems on the periphery by reaction of its mesylate derivative with 3,5-dihydroxybenzyl alcohol.


Introduction
1,1′-Methylenebis(1,2,4-triazole) is a useful compound in coordination chemistry owing to its ability to form N,N-complexes 1 and biscarbenes that are able to coordinate transition metals. 2 Functionalization of the methylene bridge would enable this compound to be transformed into bidentate ligands with a focal group, which should allow this structure to be incorporated into different macromolecules such as polymers or dendrimers.Although several methodologies have been described for the preparation of bridge-functionalized 1,1'-methylenedipyrazole and 1,1'methylenediimidazole, 3 the use of these systems in the synthesis of 1,2,4-triazole derivatives still remains a desirable goal.To the best of our knowledge, only two such examples have been described and these are 4-[bis(1,2,4-triazol-1-yl)methyl]phenol 4 (1) and methyl 3,3-bis(1,2,4triazol-1-yl)propionate 3 (2).Compound 1 was coupled to 1,3,5-tris(chlorocarbonyl)benzene to give a system that is a precursor for N-heterocyclic carbenes (NHC).However, further exploitation of this compound was not possible, probably due to the ease with which the benzylic methine bearing two triazole rings can be cleaved. 5For this reason we chose compound 2, in which the presence of a benzylic position has been avoided in order to perform convergent dendritic growth using a Fréchet methodology. 6Thus, transformation of the ester group into either a bromide or sulfonate derivative -both of which can be efficiently substituted by phenoxy groups -is necessary.
In this paper we describe the synthesis of hydroxyl, bromide and mesylate (3, 4 and 5) derivatives starting from the aforementioned ester 2. The coupling of mesylate 5 with 3,5dihydroxybenzyl alcohol to give the first generation dendron 7 is also described.

Results and Discussion
Methyl 3,3-bis(1,2,4-triazol-1-yl)propionate (2) was obtained by a double Michael addition of 1,2,4-triazole to methyl propiolate. 3Attempts to reduce the ester group using lithium aluminum hydride in refluxing THF or borane-methyl sulfide complex resulted in complete decomposition of the starting materials.However, 3,3-bis(1,2,4-triazol-1-yl)propanol (3) could be obtained in good yield (70%) using a large excess of lithium aluminum hydride in THF at -60 ºC for 25 min.(Scheme 1).Evidence for the formation of 3 was provided by 1 H NMR spectroscopy.The spectrum did not contain a signal for a methyl group and two doublet of triplets were observed at 3.60 and 2.84 ppm, which are assigned to the protons of the two methylene groups (coupling with the hydroxylic proton is observed).The bromide derivative 4 was prepared by treatment of alcohol 3 with 4 equivalents of carbon tetrabromide and 4 equivalents of triphenylphosphine in acetonitrile at rt for 24h.Purification of the product proved difficult and it could only be obtained in moderate yield (maximum 40%).On the other hand, the hydroxyl group of 3 was transformed into the corresponding mesylate derivative in 96% yield by reaction with 1.5 equivalents of MsCl and Et 3 N in THF at rt for 2h.A 1 H NMR signal at 3.03 ppm -assigned to the methyl group in the spectrum of 5 -supports the structure of this product.

ISSN 1424-6376
Page 161 The first generation dendron 7 was obtained in 75% yield by reaction of 5 with 0.5 equivalents of 3,5-dihydroxybenzyl alcohol using an excess of potassium carbonate and a catalytic amount of 18-crown-6 (18-C-6) (Scheme 2) in THF refluxed for 16h..The 1 H NMR spectrum of 7 contained a doublet at 6.46 ppm and a triplet at 6.22 ppm.These signals are assigned to the protons of the benzene ring.The peaks due to the two branches appear as one group of signals and this observation is consistent with a symmetric structure.The protons of the triazole rings and the hydrogen of the bridge have chemical shifts similar to those of 3, although the signals for the aliphatic protons of the side arms are observed at higher chemical shifts.The signal for the benzylic protons appears at 4.61 ppm as a singlet.The structure of this compound was also confirmed by 13 C NMR spectroscopy.The spectrum contains signals at 100.6 and 105.5 ppm for the para and ortho carbons, respectively, and 159.2 and 144.1 for the ipso and meta carbons of the benzene ring.A peak for the molecular ion was observed at m/z 492.2 (EI-MS) and matches the calculated molecular mass.
Experiments involving the further elaboration of dendron 7 in the synthesis of poly(Nheterocyclic carbenes) are now in progress in our laboratories.

Experimental Section
General Procedures.Solvents were purified by distillation from appropriate drying reagents before use.All reagents were used as received and without further purification.When necessary, work was carried out using standard Schlenk techniques under an atmosphere of dry argon.Melting points were determined in capillary tubes on a Gallenkamp apparatus and are uncorrected.Elemental analyses were performed on a Perkin-Elmer 2400 CHN microanalyzer.Electron Impact (EI) (working at 70 V and 200 ºC) experiments were performed on a VG Autospec instrument belonging to Servicio Interdepartamental de Investigación, Universidad Autónoma de Madrid.IR spectra were recorded on a Nicolet 550 spectrophotometer (FT-IR).NMR spectra were recorded in CDCl 3 on a Varian Inova-500 instrument with TMS or the solvent carbon signal as the standards, operating at 500 MHz for 1 H and 125 MHz for 13 C.Chemical shift are expressed in parts per million (δ).The signals were assigned with the help of difference NOE and Hetcor experiments.

3,3-Bis(1,2,4-triazol-1-yl)-1-propanol (3).
A solution of 2 (2.50 g, 11.25 mmol) in THF (50 mL) was slowly added to a mixture of LiAlH 4 (533 mg, 14.04 mmol) and THF (5 mL) at -60 ºC.The reaction mixture was stirred at that temperature for 25 min.The excess LiAlH 4 was hydrolyzed by careful addition (dropwise) of water (300 µL).The cooling bath was then removed and the solution allowed to warm up to room temperature.The solution was concentrated under vacuum until the volume was 20% of the original volume.The resulting material was centrifuged and decanted.The remaining white solid was stirred with several portions of THF (3 × 20 mL) in order to extract the maximum amount of the absorbed product.The combined organic extracts were dried over Na 2 SO 4 and the solvent removed under vacuum to afford the title alcohol 3 as a yellow oil.The pure product was obtained as a colorless solid after crystallization from CHCl 3 .Yield 70%.mp 128-130 ºC.IR (KBr, cm -