It is well established in the literature that compounds containing basic nitrogen atoms are problematic substrates for olefin metathesis. It’s assumed that the basic nitrogen atom coordinates to the metal center and interferes with catalytic activity. But what really happens to the catalyst?
A paper was published recently on the stability of Grubbs catalysts in the presence of primary amines1. It was found that primary amines displace the phosphine ligands in the first and second generation catalysts. In the first generation catalysts, both phosphine ligands were displaced to form bis-amine complexes that decomposed via bimolecular pathway similar to those described for thermal decomposition. With the second generation catalysts, only the phosphine was displaced and the NHC ligand stayed with the metal. The complex with butyl amine was isolated and, while the activity for ring closing metathesis (RCM) of diallyl malonate was minimal, it was significantly active in ring-opening metathesis polymerization, even faster than the parent second generation catalyst. Such activity is important, for example, for the production of self healing polymers in which the catalyst is exposed to primary amine curing agents.
How bad are amines? A review was published in 2007 providing an overview of successful metathesis reactions with amine containing compounds2. A special emphasis was placed on the different parameters that may influence the outcome of the reaction such as steric effects, amine basicity, and the nature of the catalyst.
So which amines are decent metathesis substrates?
The majority of examples of successful metathesis reactions are with hindered tertiary amines. The steric hindrance prevents the amine from coordinating to the metal center. Even secondary amines can undergo RCM in decent yields provided that the protecting group is big enough. Steric congestion in the vicinity of the nitrogen atom including bulky protecting groups on a neighboring atom can increase the efficiency of metathesis dramatically.
The presence of electron withdrawing groups next to the nitrogen decreases the electron density and the deactivation of the catalyst can be attenuated. Sometimes an ester group can do the trick if there is no possibility for the formation of 6-membered chelate metallacycle. Trifluoromethyl groups are among the best – even with small protecting groups like benzyl and first generation catalyst, the yields can be impressive.
Phenylamines and analogs which are in general weakly basic are much better substrates for metathesis. It’s easy to reduce the basicity of your substrate by protecting with the p-methoxyphenyl (PMP) group, which is removed under mild conditions with cerium ammonium nitrate. Even though the first generation catalysts are less stable in the presence of amines, sometimes it’s better to use them to avoid isomerization of the substrate or the product.
The next time you consider using metathesis on a nitrogen containing substrate, look at the Compain review closely before you decide on your synthetic strategy. If your amine is hindered enough you might get away without protection. And if you have to protect, carbamates and amides are not necessarily the best choice. The use of a trityl or diphenylmethyl-group could be a better alternative and there is no carbonyl group to chelate with the metal center. Conversion into the ammonium salt or running the metathesis in the presence of acids usually works3, but is not compatible with acid sensitive substrates. Another trick is to use a catalytic amount of Lewis acids. It was shown that the presence of 20 mol% Ti(OPri)4 improved dramatically the yields of RCM of amino acids4. Microwave irradiation was found to be helpful for some RCM and cross-metathesis reactions of nitrogen containing compounds.5 And you can consider using Mo-catalysts which are very stable in the presence of basic amines provided that there aren’t other functional groups in the molecule that are incompatible with the Mo-catalyst.
1 G. O. Wilson, K. A. Porter, H. Weissman, S. R. White, N. R. Sottos, and J. S. Moore, Adv. Synth. Catalysis 2009, 351, 1817
2 P. Compain, Adv. Synth. Catalysis 2007, 349, 1829
3 C. P Woodward, N. Spiccia, W. R. Jackson and A. J. Robinson Chem. Commun. 2010 ASAP.
4 Q. Yang, W.-J. Xiao, Z. Yu, Org. Lett. 2005, 7, 871.
5 R. Ettari, N. Micale, T. Schirmeister, C. Gelhaus, M. Leippe, E. Nizi, M. E. Di Francesco, S. Grasso, and M. Zappala J. Med. Chem. 2009, 52, 2157.