An important consideration in any catalyst or ligand design strategy is the ability to rapidly access structural derivatives that may enhance reactivity or selectivity in a catalytic reaction. A major attraction of the Fürstner method, and our implementation of it to prepare chiral amino alcohol-derived imidazolium salts, is the ability to introduce a wide range of N-substituents at the final stage of the synthesis simply by choice of the appropriate amine.
In preliminary studies, we have confirmed that this modular approach to chiral imidazolium salts is indeed viable and provides access to diverse N-substituents (Table 3). Indeed both hindered and unhindered anilines work well in the reaction, making possible the preparation of 145, 161–167, and 170–173. Unprotected functional groups including phenols and amides do not significantly suppress the heterocyclic interconversion. Alkylamines are also excellent reaction partners, allowing, for example, the synthesis of N-Me substituted imidazolium 169. Even hydrazines are viable, providing access to N-morpholino imidazolium 168.
3.5 Conclusion
In summary, we have developed a modular, scaleable route to the preparation of chiral aminoindanol-derived imidazolium salts, which will find use as precursors to N- heterocyclic carbene catalysts and ligands. Our eight-step route takes advantage of a chemoselective alkylation, intramolecular epoxide-opening, and a modification of the Fürstner imidazolium synthesis to achieve a robust, scaleable method for the preparation of N-aryl, N-alkyl, and N-amino imidazolium salts. We have recently established that precatalysts such as 145 can serve as catalysts for enantioselective
NHC-catalyzed homoenolate additions of enals to aldehydes, imines, and enones (Chapter 4). We anticipate that the facile access to diverse and complex imidazolium salts will facilitate our own ongoing studies aimed at improving the reactivity and selectivity of these novel annulation reactions. Furthermore, our studies provide one of the first practical routes to chiral, bicyclic imidazolium salts that may find use as novel ligands for transition metal-mediated reactions and NHC-catalyzed transformations.
3.6 References
1. Herrmann, W. A.; Kocher, C. “N-Heterocyclic Carbenes.” Angew. Chem., Int. Ed. Engl. 1997, 36 (20), 2163–2187.
2. Herrmann, W. A. “N-Heterocyclic Carbenes: A New Concept in Organometallic Catalysis.” Angew. Chem., Int. Ed. Engl. 2002, 41 (8), 1290–1309.
3. César, V. B.-L., S.; Gade, L. H. “Chiral N-Heterocyclic Carbenes as Stereo- directing Ligands in Asymmetric Catalysis.” Chem. Soc. Rev. 2004, 33 (9), 619– 636.
4. Díez-González, S.; Nolan, S. P. “Stereoelectronic Parameters aAssociated with N- Heterocyclic Carbene (NHC) Ligands: A Quest for Understanding.” Coord. Chem. Rev. 2007, 251 (5–6), 874–883.
5. Glorius, F. N-Heterocyclic Carbenes in Transition Metal Catalysis. Springer: New York, NY, 2007.
6. de Fremont, P.; Marion, N.; Nolan, S. P. “Carbenes: Synthesis, Properties, and Organometallic Chemistry.” Coord. Chem. Rev. 2009, 253 (7–8), 862–892.
7. Díez-González, S.; Marion, N.; Nolan, S. P. “N-Heterocyclic Carbenes in Late Transition Metal Catalysis.” Chem. Rev. 2009, 109 (8), 3612–3676.
8. Breslow, R. “On the Mechanism of Thiamine Action .4. Evidence from Studies on Model Systems.” J. Am. Chem. Soc. 1958, 80 (14), 3719–3726.
9. Enders, D.; Balensiefer, T. “Nucleophilic Carbenes in Asymmetric Organocatalysis.” Acc. Chem. Res. 2004, 37 (8), 534–541.
10. Nair, V.; Bindu, S.; Sreekumar, V. “N-Heterocyclic Carbenes: Reagents, Not Just Ligands!.” Angew. Chem., Int. Ed. Engl. 2004, 43 (39), 5130–5135.
11. Enders, D.; Niemeier, O.; Henseler, A. “Organocatalysis by N-Heterocyclic, Carbenes.” Chem. Rev. 2007, 107 (12), 5606–5655.
12. Marion, N.; Díez-González, S.; Nolan, I. P. “N-Heterocyclic Carbenes as Organocatalysts.” Angew. Chem., Int. Ed. Engl. 2007, 46 (17), 2988–3000.
13. Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. “Oxazolines as Chiral Building Blocks for Imidazolium Salts and N-Heterocyclic Carbene Ligands.” Chem. Commun. 2002, 22, 2704–2705.
14. Burstein, C.; Lehmann, C. W.; Glorius, F. “Imidazo[1,5-a]Pyridine-3-Ylidenes - Pyridine Derived N-Heterocyclic Carbene Ligands.” Tetrahedron 2005, 61 (26), 6207–6217.
15. Tewes, F.; Schlecker, A.; Harms, K.; Glorius, F. “Carbohydrate-Containing N- Heterocyclic Carbene Complexes.” J. Organomet. Chem. 2007, 692 (21), 4593– 4602.
16. Seiders, T. J.; Ward, D. W.; Grubbs, R. H. “Enantioselective Ruthenium-Catalyzed Ring-Closing Metathesis.” Org. Lett. 2001, 3 (20), 3225–3228.
17. Gillingham, D. G.; Hoveyda, A. H. “Chiral N-Heterocyclic Carbenes in Natural Product Synthesis: Application of Ru-Catalyzed Asymmetric Ring-Opening/Cross- Metathesis and Cu-Catalyzed Allylic Alkylation to Total Synthesis of Baconipyrone C.” Angew. Chem., Int. Ed. Engl. 2007, 46 (21), 3860–3864.
18. Wurtz, S.; Lohre, C.; Frohlich, R.; Bergander, K.; Glorius, F. “IBiox[(-)-menthyl]: A Sterically Demanding Chiral NHC Ligand.” J. Am. Chem. Soc. 2009, 131 (24), 8344–8345.
19. Chaulagain, M. R.; Sormunen, G. J.; Montgomery, J. “New N-Heterocyclic Carbene Ligand and Its Application in Asymmetric Nickel-Catalyzed Aldehyde/Alkyne Re- ductive Couplings.” J. Am. Chem. Soc. 2007, 129 (31), 9568–9569.
20. Chow, K. Y. K.; Bode, J. W. “Catalytic Generation of ActivatedCarboxylates: Direct, Stereoselective Synthesis of #-Hydroxyesters from Epoxyaldehydes. J. Am. Chem. Soc. 2004, 126 (26), 8126–8127.
21. Sohn, S. S.; Bode, J. W. “Catalytic Generation of Activated Carboxylates from Enals: A Product-Determining Role for the Base.” Org. Lett. 2005, 7 (18), 3873– 3876.
22. Sohn, S. S.; Bode, J. W. “N-Heterocyclic Carbene catalyzed C–C Bond Cleavage in Redox Esterifications of Chiral Formylcyclopropanes.” Angew. Chem., Int. Ed. Engl. 2006, 45 (36), 6021–6024.
23. Bode, J. W.; Sohn, S. S. “N-Heterocyclic Carbene-Catalyzed Redox Amidations of !-Functionalized Aldehydes with Amines.” J. Am. Chem. Soc. 2007, 129 (45), 13798–13799.
24. Sohn, S. S.; Rosen, E. L.; Bode, J. W. “N-Heterocyclic Carbene-Catalyzed Generation of Homoenolates: "-Butyrolactones by Direct Annulations of Enals and Aldehydes.” J. Am. Chem. Soc. 2004, 126 (44), 14370–14371.
25. He, M.; Bode, J. W. “Catalytic Synthesis of "-Lactams via Direct Annulations of Enals and N-Sulfonylimines.” Org. Lett. 2005, 7 (14), 3131–3134.
26. He, M.; Struble, J. R.; Bode, J. W. “Highly Enantioselective Azadiene Diels-Alder Reactions Catalyzed by Chiral N-Heterocyclic Carbenes.” J. Am. Chem. Soc. 2006, 128 (26), 8418–8420.
27. He, M.; Uc, G. J.; Bode, J. W. “Chiral N-Heterocyclic Carbene Catalyzed, Enantioselective Oxodiene Diels-Alder Reactions with Low Catalyst Loadings.” J. Am. Chem. Soc. 2006, 128 (47), 15088–15089.
28. Chiang, P. C.; Kaeobamrung, J.; Bode, J. W. “Enantioselective, Cyclopentene- Forming Annulations via NHC-Catalyzed Benzoin–Oxy-Cope Reactions.” J. Am. Chem. Soc. 2007, 129 (12), 3520–3521.
29. He, M.; Bode, J. W. “Enantioselective, NHC-Catalyzed Bicyclo-#-Lactam Formation via Direct Annulations of Enals and Unsaturated N-Sulfonyl Ketimines.” J. Am. Chem. Soc. 2008, 130 (2), 418–419.
30. Rommel, M.; Fukuzumi, T.; Bode, J. W. “Cyclic Ketimines as Superior Electrophiles for NHC-Catalyzed Homoenolate Additions with Broad Scope and Low Catalyst Loadings.” J. Am. Chem. Soc. 2008, 130 (51), 17266–17267.
31. Kaeobamrung, J.; Bode, J. W. “Stereodivergency of Triazolium and Imidazolium- Derived NHCs for Catalytic, Enantioselective Cyclopentane Synthesis.” Org. Lett. 2009, 11 (3), 677–680.
32. Struble, J. R.; Kaeobamrung, J.; Bode, J. W. “Synthesis of an N-Mesityl Substituted Chiral Imidazolium Salt for NHC-Catalyzed Reactions.” Org. Lett. 2008, 10 (5), 957–960.
33. Burstein, C.; Glorius, F. “Organocatalyzed Conjugate Umpolung of !,#-Unsaturated Aldehydes for the Synthesis of "-Butyrolactones.” Angew. Chem., Int. Ed. Engl. 2004, 43 (45), 6205–6208.
34. Honjo, T. “Asymmetric Benzoin Reactions with N-Heterocyclic Carbene Catalysts.” J. Synthetic Org. Chem. Jpn. 2007, 65 (4), 370–371.
35. Rovis, T.; Read de Alaniz, J. “The Catalytic Asymmetric Intramolecular Stetter Reaction.” Synlett. 2009, 8, 1189–1207.
36. Struble, J. R.; Bode, J. W. “Formal Synthesis of Salinosporamide A via NHC- Catalyzed Intramolecular Lactonization.” Tetrahedron 2009, 65 (26), 4957–4967. 37. Arduengo, A. J.; Krafczyk, R.; Schmutzler, R.; Craig, H. A.; Goerlich, J. R.;
Marshall, W. J.; Unverzagt, M. “Imidazolylidenes, Imidazolinylidenes and Imidazolidines.” Tetrahedron 1999, 55 (51), 14523–14534.
38. Hirano, K.; Urban, S.; Wang, C.; Glorius, F. “A Modular Synthesis of Highly Substituted Imidazolium Salts.” Org. Lett. 2009, 11 (4), 1019–1022.
39. Kuhn, N.; Kratz, T. “Synthesis of Imidazol-2-Ylidenes by Reduction of Imidazole- 2(3h)-Thiones.” Synthesis 1993, 6, 561–562.
40. Nyce, G. W.; Csihony, S.; Waymouth, R. M.; Hedrick, J. L. “A General and Versatile Approach to Thermally Generated N-Heterocyclic Carbenes.” Chem. Eur. J. 2004, 10 (16), 4073–4079.
41. Fürstner, A.; Alcarazo, M.; César, V.; Lehmann, C. W. “Convenient, Scalable and Flexible Method for the Preparation of Imidazolium Salts with Previously Inacces- sible Substitution Patterns.” Chem. Commun. 2006, 20, 2176–2178.
42. Song, Z. Q.; Zhao, M. Z.; Tillyer, R.; Desmond, R.; Tschaen, D. M.; Devine, P.; Frey, L.; Heid, R.; Foster, B.; Li, J.; Volante, R.; Dolling, U. H.; Grabowski, E. J. J.; Reider, P. J., “Practical Asymmetric Synthesis of an Endothelin Receptor Antagonist.” J. Org. Chem. 1999, 64 (26), 9658–9667.
43. Hashimoto, N.; Kanda, A. “Practical and Environmentally Friendly Epoxidation of Olefins Using Oxone.” Org. Process Res. Dev. 2002, 6 (4), 405–406.
44. Potter, G. W.; Monro, A. M. “A Synthetic Entry into the 2- and 3-Substituted-Methyl 2,3-Dihydro-1,4-Benzoxazine Series.” J. Heterocycl. Chem. 1972, 9, 299–301. 45. Wang, Z. X.; Tu, Y.; Frohn, M.; Zhang, J. R.; Shi, Y. “An Efficient Catalytic
Asymmetric Epoxidation Method.” J. Am. Chem. Soc. 1997, 119 (46), 11224– 11235.
46. Fürstner, A.; Alcarazo, M.; César, V.; Krause, H. “Preparation of a Non-Symmetrical i m i d a z o l i u m S a l t : 1 - A d a m a n t y l - 3 - M e s i t y l - 4 , 5 - D i m e t h y l i m i d a z o l i u m Tetrafluoroborate.” Org. Synth. 2008, 85, 34–44.