Transition metal catalyzed cyclotrimerization to new pyridine ligands for asymmetric hydrogenation
New fused pyridine ring systems for the application as ligands in iridium catalyzed asymmetric hydrogenation have been synthesized with cyclotrimerization as a key step. This proved to be a efficient method for varying the wanted substitution patterns in one step.
Firstly, alkynenitriles 3a and 3b were synthesized from commercially available starting materials in 24 and 38% overall yields, respectively, as shown in figure 1. The yields for the individual steps are given in the figure.
Figure 1: Synthesis of the alkynenitriles 3a and 3b.
The starting butyn alcohol was tosylated to 1, which was further converted to the iodide 2a by a Finkelstein reaction. Iodide 2a was then reacted with ethyl cyanoacetate in an alkylation reaction to form 3a. Alkynenitrile 3b was synthesized in a similar manner from the pentyne chloride.
By variyng the alkynes, were 3a and 3b converted into eight new structural entities by cyclotrimerization in 17-48% yields, as shown in figure 2.
Figure 2: Cyclotrimerization of 3 with various alkynes towards 4a-h.
The reactions shown in figure 2 were conducted both in a pressure vial, and by slow addition methods. CpCo(CO)2 was used as the catalyst, and activation of the pre-catalyst was done by irradiation. It was shown that usage of a pressure vial in general produced 4 in better yields than the slow addition method. When monosubstituted alkynes were employed, the reactions showed excellent regioselectivity towards the 2-substituted regioisomers, in accordance to mechanistic models described in the literature. Further improvements of the yields by using other catalysts (Fe(OAc)2/ligand, Cp*RuCl(COD) and CpCo(COD)) and reaction conditions did not succeed.
Due to good results from preliminary testing of 4d as a ligand in asymmetric hydrogenations, evaluation of the pyridine esters 4a-4c as ligands were therefore wanted. Separation into pure enantiomers via the diastereomers were attempted as described in figure 3.
Figure 3: Attempted separation of the enatiomers of 4b and 4c.
Reduction of the pyridine esters 4b and 4c yielded the alcohols 5b and 5c in 48 and 50% yield, respectively. The alcohols 5b and 5c were further reacted with (S)-camphanic chloride to yield 1:1 diastereomeric mixtures of 6b and 6c in 47 and 32% yield, respectively. The diastereomers (R)-6b and (S)-6b was obtained pure in small amounts so that rotation could be measured, and hydrolysis back to (R)-5b and (S)-5b could be attempted. Here, total desilylation was observed. Separation of (R)-6c and (S)-6c were not successful with conventional chromatography. Based on these results is chiral preparative HPLC recommended as the method of choice for achieving pure enantiomers. The pyridines 4a-4c will be tested as ligands in asymmetric hydrogenation in Sweden, by professor Pher Andersson.
Place, publisher, year, edition, pages
Institutt for kjemi , 2013. , 209 p.
IdentifiersURN: urn:nbn:no:ntnu:diva-22495Local ID: ntnudaim:8527OAI: oai:DiVA.org:ntnu-22495DiVA: diva2:649739
Gautun, Odd Reidar, Førsteamanuensis