ORGANIC LETTERS
Formal Olefination and Acylaziridination of Imidazolones†
2010 Vol. 12, No. 12 2718-2721
Xing Dai,* Michael W. Miller, and Andrew W. Stamford Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033
[email protected] Received April 6, 2010
ABSTRACT
The first formal olefination and acylaziridination of imidazolones were obtained by cycloaddition of cyclic nitrones with alkenes and alkynes, respectively.
The imidazolone and imidazolidinone skeletons are key structural motifs that appear in the core structures of natural products and drug candidates. For example, alkaloids Kottamides A-C (1), isolated from the endemic ascidian PycnoclaVella kottae, have exhibited anti-inflammatory and antimetabolic activity as well as cytotoxicity toward tumor cell lines (Figure 1).1 For recent pharmaceutical candidates, the spiro-condensed imidazolone (2) is an example of a glycine transporter inhibitor, a potential therapeutic agent for Schizophrenia,2 while the 2,3,5-substituted imidazolidin4-one (3) is a β-secretase (BACE-1) inhibitor, which has potential for treating Alzheimer’s disease.3 Despite the importance of these molecules, very few methods have been developed to functionalize these heterocycles,4 especially for 1H-imidazol-5(2H)-ones. In this paper, we describe the preparation of two novel imidazolone derivatives 5 and 6 † This paper is dedicated to Professor Huw M. L. Davies on the occasion of his 54th birthday. (1) Appleton, D. R.; Page, M. J.; Lambert, G.; Berridge, M. V.; Copp, B. R. J. Org. Chem. 2002, 67, 5402. (2) (a) Blunt, R.; Cooper, D. G.; Porter, R. A.; Wyman, P. A. WO 2009034061, 2009. (b) Ahmad, N. M.; Lai, J. Y. Q.; Andreotti, D.; Marshall, H. R.; Nash, D. J.; Porter, R. A. WO 2008092876, 2008. (c) Coulton, S.; Porter, R. A. WO 2008092872, 2008. (3) Barrow, J. C.; Rittle, K. E.; Ngo, P. L.; Selnick, H. G.; Graham, S. L.; Pitzenberger, S. M.; McGaughey, G. B.; Colussi, D.; Lai, M.-T.; Huang, Q.; Tugusheva, K.; Espeseth, A. S.; Simon, A. J.; Munshi, S. K.; Vacca Jo, P. ChemMedChem 2007, 2, 995. (4) Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T. HelV. Chim. Acta 1987, 70, 237.
10.1021/ol1007923 2010 American Chemical Society Published on Web 05/19/2010
Figure 1. Biologically active compounds.
that are made from the cycloaddition of heterocyclic nitrone 4 with alkenes and alkynes, respectively (Figure 2). The 1,3-dipolar cycloaddition reaction of nitrones has attracted considerable attention as one of the most important methodologies for the construction of N-containing heterocycles.5 For instance, the [3+2] cycloaddition of nitrones with alkenes is a classic reaction for the synthesis of
Scheme 1. Formation of 11
Figure 2. Novel products from imidazolone nitrones.
isoxazolidines 7, which have been utilized to access β-amino alcohols, and both pyrrolizidine and indolizidine alkaloids (Figure 3). On the other hand, isoxazolines 8 that are cycloaddition products from nitrones and alkynes tend to undergo rearrangement due to their thermal instability.6
Figure 3. Classic [3+2] cycloaddition of nitrones.
We have been interested in the synthesis of imidazolone derivatives that could impact our current project targeting type-II diabetes. One of our model studies was to test a 1,3dipolar reaction on spiro-imidazolone 9 (Scheme 1).7 When the [3+2] adduct 108 was treated with base, trans-olefinated product 11 was isolated after acidic workup in 80% yield, along with a minor side product 14 (
