Highly Enantioselective Hydrogenation of Acyclic Imines Catalyzed by Ir-f-Binaphane Complexes

Although great accomplishments have been achieved in the highly enantioselective hydrogenation of prochiral alkenes and ketones in the last few decades,[1] limited progress has been made in the asymmetric hydrogenation of imines.[2] A number of efficient asymmetric catalysts for the reduction of alkenes and ketones are ineffective for the hydrogenation of related imine compounds. Since chiral amines are important functionalities in many biologically active molecules, the development of practical methods for the hydrogenation of imines is extremely important in organic synthesis. Among some notable achievements in the field, Buchwald and co-workers[3] have developed a chiral titanocene catalyst for the reduction of imines, and the system is highly effective for the hydrogenation of cyclic imines. A number of group VIII transition metal catalysts that bear chiral chelating phosphanes have been explored for the hydrogenation of imines, and these systems generally have a very limited substrate scope.[4, 5] The highly enantioselective hydrogenation of N-(phenylethylidene)aniline (89 % ee) and related imines by using an Ir ± phosphaneoxazoline complex as the catalyst have been reported by Pfaltz and co-workers.[6] A significant industrial process that uses the Ir-catalyzed asymmetric hydrogenation of an N-arylimine (106 turnovers and 80 % ee) has been developed.[7] Despite these impressive advances, the lack of highly enantioselective and reactive catalysts with broad substrate scopes for the hydrogenation of imines is still a major problem in asymmetric catalysis. Herein we report a highly enantioselective hydrogenation of Narylimines catalyzed by Ir complexes with a novel chiral ferrocene phosphane group and an important additive effect for the Ir-catalyzed asymmetric hydrogenation of imines. Recently we made a chiral phosphane ligand, binaphane, and used it for the Rh-catalyzed highly enantioselective hydrogenation of enamides.[8] However, Rh and Ir complexes of chiral binaphane are not effective for the hydrogenation of imines. To alter the steric and electronic properties of the binaphane ligand, we envisioned that the introduction of a ferrocene backbone would be helpful. The new air-stable, chiral 1,1'-bisphosphanoferrocene (1; abbreviated as f-binaphane) was then prepared by using a similar route used in the synthesis of binaphane (Scheme 1). USA 1993, 90, 10922 ± 10 926; b) H. P. Nestler, P. A. Bartlett, W. C. Still, J. Org. Chem. 1994, 59, 4723 ± 4724. [7] a) H. E. Blackwell, L. PeÂrez, R. A. Stavenger, J. A. Tallarico, E. CopeEatough, M. A. Foley, S. L. Schreiber, Chem. Biol. , submitted; b) P. A. Clemons, A. N. Koehler, B. K. Wagner, T. G. Sprigings, D. R. Spring, R. W. King, S. L. Schreiber, M. A. Foley, Chem. Biol. , submitted. [8] R. A. Stavenger, S. L. Schreiber, Angew. Chem. 2001, 113, 3525 ± 3529; Angew. Chem. Int. Ed. 2001, 40, 3417 ± 3421. [9] M. A. McKervey, D. N. Russell, M. F. Twohig, J. Chem. Soc. Chem. Commun. 1985, 491 ± 492. [10] R. Johansson, B. Samuelsson, J. Chem. Soc. Perkin Trans. 1 1984, 2371 ± 2374. [11] Still and co-workers reported tag insertion into a support-bound tetrapeptide during the encoding process, in a ratio of 1:8 with tag inserted into the support (PS bead diameter 50 ± 100 mm, loading 100 pmol gy1). The authors used substantially less diazoketone tag (1 pmol tag/bead) to encode their synthesis resin than we found to be sufficient for 500 ± 600 mm PS macrobeads (20 nmol tag/bead), presumably due to a more efficient heterogeneous insertion reaction on smaller beads. See refs. [6b] and [7]. [12] For a review of RhII-catalyzed carbene reactions, see: J. Adams, D. M. Spero, Tetrahedron 1991, 47, 1765 ± 1808. [13] Direct silylation and GC analysis of compounds cleaved from beads with HF ± py without CAN treatment indicated only negligible amounts of tag silyl ethers, which ruled out the compound cleavage step as a major tag-cleavage event. [14] Prepared by an EDC-mediated coupling between 5-amino-1-pentanol and p-tolylacetic acid in CH2Cl2 in the presence of triethylamine and 4-dimethylaminopyridine (DMAP). See: J. C. Sheehan, P. A. Cruickshank, G. L. Boshart, J. Org. Chem. 1961, 26, 2525 ± 2528. [15] Attempts to determine the structure of the tag-inserted compound have been unsuccessful so far. However, we postulate that an aromatic-ring and/or NyH insertion reaction occurred. See ref. [12]. [16] Given the different efficiencies of the homogeneous and heterogeneous tag-cleavage reactions, we could not determine quantitatively if more tag was inserting into the compound rather than the bead, or vice versa. [17] This discrepancy can be attributed to either unsuccessful chemical reaction in one or more of the library steps and/or poor ionization by MS, and serves as a reminder that encoding records the sequence of chemical reactions to which a bead is subjected, not the structure of the compound. [18] The structures assigned to the 108 samples can be found in the Supporting Information. [19] Supporting Information available: Representative encoding and decoding protocols, 1H NMR spectroscopy, LC, and GC data, and full details of the partial library decoding.