CORDIS - EU research results

Metal and Organo-Catalysts for the Production of 1,2-Diamines

Final Report Summary - MOC-DA (Metal and Organo-Catalysts for the Production of 1,2-Diamines)

The research carried out has been focused on the catalytic direct diamination of olefins to access vicinal diamines in a enantioselective manner.

Firstly, the project was directed towards the study of a novel, intramolecular anionic [3+2] cycloaddition between an anionic amidine and an alkene to generate vicinal diamines (Scheme 1). During this process, an anionic imidazolidine intermediate 3 would be produced and further reaction with electrophiles would introduce different functionalities into the molecule. The preparation of the starting material (compounds 2) for cycloaddition reaction was problematic and only in few cases were compounds 2 accessible. Unfortunately cycloaddition reaction of these substrates under different conditions did not occur.

Secondly, a metal catalysed oxidative diamination reaction was proposed to access 1,2-diamines by using amides with N bearing a good leaving group (OCOAr) as smart re-oxidants for Os (VI). Previous to this, I gained some experience working with sensitive catalytic reactions and I carried out the synthesis of the natural product hygromycin A with an aminocyclitol skeleton in its structure, which could be accessed by using a catalytic tethered aminohydroxylation (TA) reaction. The TA reaction was studied on compound 4 and oxazolidinone 5 was obtained in excellent yield and selectivity with only 1 mol% of Os (VI) catalyst in aqueous butanol at room temperature (Scheme 2). The reproducibility and ease of handling of this reaction is noteworthy, as well as that it was possible to scale it up to 2 grams. The total synthesis of the natural product hygromycin A was completed in 27 linear steps and in 10 % overall yield. This work has been published in one of the most important journals in organic chemistry: Angew Chem Int Ed 2009, 48, 6507-6510.

The osmium catalysed direct diamination of olefins to access to vicinal diamines 12 in a enantioselective manner was studied next (Scheme 3). Bis-imido complex 8 would be the proposed intermediate in the diamination reaction and it would react with the alkene to afford 1,2-diamines. The formation of complex 12 was proposed to be achieved in two ways:
1. Firstly, a N=Os bond would be formed by oxidation of Os(VI) with a carbamate reoxidant to afford mono-imido complex 7. The second nitrogen substituent would be introduced by further intramolecular condensation of the amide group with Os=O to give 8.
2. An innovative procedure was proposed where two catalytic oxidations of Os take place. In this case, bis-imido complexes 8 would be prepared from bis-carbamates 9 by oxidation of Os (IV) using one re-oxidant to give 10 followed by a second oxidation of Os (VI) using another re-oxidant. This procedure promises to be a very novel and interesting procedure, since the use of Os (IV) has not been reported before in the catalytic oxidation of alkenes.

The stoichiometric diamination reaction would be first studied and if success, catalysis would be then introduced. Starting materials 6 and 9 were easily synthesised from commercially available compounds. However, when amido-carbamate 6 was subjected to stoichiometric diamination reaction it was unsuccesful and alkene starting material was recovered.

To study this reaction and clarify the origin of the problem an experiment was carried out in which different oxidation states of osmium have different colours; glycolate-quinuclidine complex 13 that formally contained Os (VI) is green, while azaglycolate Os (VIII) complex is a brown colour. Oxidation of 13 using re-oxidant 6 appeared to be effective and a change of colour from green to browm was observed; however, after addition of an alkene no desired diaminated product was detected (Scheme 4). To rationalise this result we atributed some difficulties during the condensation step after reoxidation of Os (VI) to Os (VIII). This step generally requieres a more reactive nitrogen source that an amide group; then, a variant of the reaction was carried out using triphenyl phosphinimides. Again diamine desired product was not isolated. The stoichiometric diamination of alkenes using compound 9 as a nitrogen source in the presence of Os (IV) was also examined and gave recovery of starting material, probably because Os (IV) is not reactive enough. Although the results obtained during the diamination project were not encouranging, there are still some experiments and ideas that was fruitful and further studies in this area will be performed.

Finally and to complete the skills I gained in metal oxidation of alkenes, the aminohydroxylation reaction of styrenes using a re-oxidant source based on the amino-acid valine 16 was studied (Scheme 5). This was especially interesting as it is the first use of an amino acid as the nitrogen-donating unit. Synthesis of 16 was easily achieved starting from (L)-valine in a 3-step procedure in 52 % overall yield. Continuing with preliminary studies made in the group, we studied the AA reaction of 4-methoxystyrene and re-oxidant 16. The best conditions were obtained when 5 mol% of potassium osmate and 5 % (DHQD)2PHAL ligand in MeCN:H2O at room temperature were used and amino alcohols 17 and 18 (13:1) were isolated in 90 % yield and with good diastereoselectivity (11:1) for 17. The compability of this process was shown using different groups at the aryl position of the alkene and gave excellent results with styrene, 4-acetoxystyrene and 2-vinylnaphthalene. More substituted systems gave complete regioselectivity but with moderate diastereoselectivity and yields.