Towards benign syntheses of bipyridines: versatile approach to supramolecular building blocks Gareth W. V. Cave a, * and Colin L. Raston b, * a School of Biomedical and Natural Sciences, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK b School of Biomedical and Chemical Sciences, University of Western Australia, Crawley, Perth, WA 6009, Australia Received 20 December 2004; revised 10 February 2005; accepted 15 February 2005 Abstract—Chiral and achiral bipyridines are readily accessible via a solvent-free Michael addition involving solid NaOH, followed by treatment with ammonium acetate in acetic acid, as a Ôone potÕ more benign protocol, affording pure products in high yield, typically >80%. Ó 2005 Elsevier Ltd. All rights reserved. 1. Introduction Bipyridine chiragens have been complexed to an exten- sive number of metals over the latter two decades. 1–6 Such complexes, especially those derived from pinene and camphor, have been shown to form supramolecular helicates, 4,5 with a growing number demonstrating cata- lytic properties. 6 Conventional synthesis of such bipyri- dines from chiral exocyclic enone precursors use volatile organic solvents, harsh conditions, have low atom effi- ciency and display only moderate to low yields. 2,7–9 In embracing the principals of green chemistry, 10 we have developed a facile synthesis to such compounds involv- ing a solvent-free Michael addition reaction, which re- sults in a dramatic improvement in yield relative to traditional methods. Bergman and coworkers 11 reported a three step synthesis of mono-substituted 2,2 0 -bipyri- dines via a dihydropyran from an aldol condensation product and sequential nitrogen insertion to form the substituted pyridine. Although this method displays moderate yields (21–57%) it is limited to aryl substitu- tion at the 4-position of one of the pyridine units. Bipyridines are typically synthesized via a Friedla ¨nder reaction, whereby an aminoaldehyde and an enolizable ketone undergo a double condensation; 6 or from the reaction between an exocyclic enone and an acetylpyri- dinepyridinium halide in the presence of ammonium acetate; a variation on the Kro ¨hnke condensation reac- tion. 2,12 These reactions seldom afford an overall yield greater than 50% and are generated by multi-step pro- cesses which inevitably lead to an expensive, time con- suming protocol with considerable waste and are energy intensive. In an age where there is a growing concern surrounding the long-term effects arising from the unsustainable use and subsequent disposal of organic solvents, a new more benign field of research has inevitably awoken. The internationally recognized 12 principles of green chemis- try, as defined by Anastas and Warner, 10 has led to sig- nificant advances in energy conservation and waste minimization, as defined by the E factor (=waste (kg)/ 1 kg product). 13 Synthetically this has led to the evolu- tion and development of viable alternative reaction media to traditional volatile organic solvents; a field of research dominated by ionic liquids. 14 We too have investigated and continue to probe for more benign bio-sustainable reaction media. 15 However, we have pursued a paradoxical shift away from conventional synthetic methodologies, by engaging the use of sol- vent-free reactions. 16 By eliminating the need for solvent and thereby minimizing waste and cost, we have found that many conventional reactions readily proceed in near quantitative yield with minimal or no workup. 15–17 Continuing on from our advances in the ÔgreenÕ synthe- sis of triarylpyridine molecules we sought to extend our studies to bipyridines, adopting the principals of green chemistry. 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.02.081 Keywords: Green chemistry; Solvent free; Pyridines; Ketones. * Corresponding authors. Tel.: +61 8 9380 3161; fax: +61 8 9380 1005 (C.L.R.); tel.: +44 115 848 3242; fax: +44 115 848 6636 (G.W.V.C.); e-mail addresses: clraston@chem.uwa.edu.au; gareth.cave@ntu.ac.uk Tetrahedron Letters 46 (2005) 2361–2363 Tetrahedron Letters