Novel Methinic Functionalized and Dendritic C-Scorpionates

The study of chelating ligands is undoubtedly one of the most significant fields of research in chemistry. The present work is directed to the synthesis of new functionalized derivatives of tripodal C-scorpionate compounds. Tris-2,2,2-(1-pyrazolyl)ethanol, HOCH2C(pz)3 (1), one of the most important derivatives of hydrotris(pyrazolyl)methane, was used as a building block for the synthesis of new functionalized C-scorpionates, aiming to expand the scope of this unexplored class of compounds. The first dendritic C-scorpionate was successfully prepared and used in the important industrial catalytic reactions, Sonogashira and Heck C-C cross-couplings.

The first step was the protection of the phenol of 4-hydroxybenzaldehyde. By reacting 4hydroxybenzaldehyde with one equivalent of tertbutyldimethylsilanechloride and one equivalent of imidazole in THF we received the tert-butyl dimethyl silyl protected 4-(bromomethyl)phenol (see Scheme S1). In 13 C NMR we saw a change of the signal of the carbon in the meta position to the phenol. It was changed down field from 116.06 ppm for 4-hydroxybenzaldehyde to 120.37 ppm for the product.
By reducing the phenol protected molecule with one equivalent of NaBH4 in THF over night we managed to receive the corresponding alcohol compound (see Scheme S1) with a retained protection on the phenol function. Both in 13 C and in 1 H NMR there were large differences between the starting material and product. In 1 H NMR the aldehyde disappeared at 9.83 ppm and the benzyl alcohol function appeared at 4.57 ppm. In 13 C NMR the same difference was expected and seen. The aldehyde shifted up field from 190.58 ppm to 64.96 ppm for the benzyl alcohol.
The next step was to make a substitution reaction of the alcohol for a better leaving group. Here we might have been a bit too cautious and should probably have gone directly to the bromide compound and spared ourselves one reaction step. But we did not and instead we reacted the alcohol compound with one equivalent of tri-fluoroacetic anhydride in THF. The reaction mixture was stirred for 40 minutes at reflux to yield us the CF3COO derivative (see Scheme S1). In 1 H NMR we saw the peak for the benzyl group shift from 4.57 ppm to 5.31 ppm for the product.
Another nucleophilic substitution to receive an even better leaving group was done by reacting the above compound in refluxing THF for 14 hours with one equivalent of LiBr giving us the desired tert-butyl dimethyl silyl protected 4-(bromomethyl)phenol (see Scheme S1). In 1 H NMR we once again saw a change of the benzyl group. This time it changed up field from 5.31 ppm to 4.51 ppm which was very similar to the previous value with the alcohol function. In 13 C we also saw a change up field from 69.57 ppm for the benzyl group on the starting material to 33.93 ppm for the product.
Finally, we are at an important step of this synthetic route since we are about to graft the scorpionate onto the phenolic species. A slurry was made with NaH in THF. To this slurry was slowly added a mixture containing one equivalent of alcohol scorpionate and the tert-butyl dimethyl silyl desired protected 4-(bromomethyl)phenol. The reaction was left stirring for 17 hours before we received tert-butyl dimethyl silyl protected (tris-2,2,2-(pyrazol-1-yl)ethoxy)-4-phenol (see Scheme S1). In 1 H NMR we observed a minor change of the benzyl function from 4.51 ppm to 4.42 ppm for the product. In 13 C NMR the change of the benzyl function was more noteworthy since the starting material was at 33.93 ppm and in the product the material ended up at 77.59 ppm.
One tiny little step left to have the product that we started the crusade for. This step was a deprotection of the phenol function and was done by solubilizing the tert-butyl dimethyl silyl protected 4-(2,2,2-tris(1-pyrazolyl)ethoxymethyl)phenol in THF and cooling it in an ice-bath.

Preparation of N-tosylaziridine from ethanolamine
N-tosylaziridine was obtained by a two steps pathway:

1) Synthesis of N,O-bistosylethanolamine, TsNHCH2CH2OTs.
To a stirred solution of tosylchloride (6.17 g, 32.36 mmol, 2.1 eq) in pyridine (4 mL) cooled at -30 ºC was added dropwise a solution of ethanolamine (993 μL, 16.18 mmol, 1 eq) in pyridine (3 mL). The resulting mixture was stirred 1 h at -10 ºC, overnight, at 0 ºC. Crushed ice and CHCl3 (10 mL) were added and the mixture stirred for 15 minutes. The organic phase was separated and washed with H2O (3 x 10 mL), glacial acetic acid (5 mL) and water (10 mL), dried over Na2SO4 and evaporated to yield an orange oil that was triturated in pentane affording a white off solid (81%). The apical proton of the variably ring substituted hydrotris(pyrazolyl)methane has been successfully removed (Reaction A) and the carbanion carboxylated to obtain the lithium carboxylate Li[OOC-C(pz)3]. This derivative has also been achieved by nucleophilic substitution of trichloroacetic acid (reaction B) or by oxidation of the terminal alcohol tris-2,2,2-(1-pyrazolyl)ethanol (reaction C). However, at the final stage, the addition of acid to the carboxylate solution results in the formation of the starting hydrotris(pyrazolyl)methane.
A proposed decarboxylation mechanism assisted from the nitrogen atom of an adjacent pyrazolyl ring is shown in Scheme S5: the weakly basic nitrogen could promote the activation of the carboxylic group and the decarboxylation process. This decomposition mechanism from the intermediate carboxylate is suggested by the detection of the quantitative formation of hydrotris(pyrazolyl)methane, HC(pz)3, from reaction of (2) with KOH and KMnO4 in water and subsequent acidification with HCl (reaction C).
In order to explore the synthetic strategies of functionalization of hydrotris(pyrazolyl)methane, a modification of a previous reaction B (Scheme 4) has been carried out: 3 eq of 3,5-dimethylpyrazole have been reacted with trichloro acetonitrile. The reaction does not proceed to completion but appears promising to further studies.