Organolanthanide-Catalyzed Intramolecular Hydroamination

Chemical Reviews 2013 113 (8), 6864-6900 ... Kuntal Manna , William C. Everett , George Schoendorff , Arkady Ellern .... Organo-f,d-Mediated Synthesis...
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Organolanthanide-Catalyzed Intramolecular Hydroamination/ Cyclization/Bicyclization of Sterically Encumbered Substrates. Scope, Selectivity, and Catalyst Thermal Stability for Amine-Tethered Unactivated 1,2-Disubstituted Alkenes Jae-Sang Ryu,† Tobin J. Marks,*,† and Frank E. McDonald*,‡ Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, and Department of Chemistry, Emory University 1515 Pierce Drive, Atlanta, Georgia 30322 [email protected] Received September 27, 2003

This paper reports the organolanthanide-catalyzed intramolecular hydroamination/cyclization of amine-tethered unactivated 1,2-disubstituted alkenes to afford the corresponding mono- and disubstituted pyrrolidines and piperidines using coordinatively unsaturated complexes of the type (η5-Me5C5)2LnCH(TMS)2 (Ln ) La, Sm), [Me2Si(η5-Me4C5)2]SmCH(TMS)2, and [Me2Si(η5-Me4C5)(tBuN)]LnE(TMS)2 (Ln ) Sm, Y, Yb, Lu; E ) N, CH) as precatalysts. [Me2Si(η5-Me4C5)(tBuN)]LnE(TMS)2 mediates intramolecular hydroamination/cyclization of sterically demanding amino-olefins to afford disubstituted pyrrolidines in high diastereoselectivity (trans/cis ) 16/1) and good to excellent yield. In addition, chiral C1-symmetric organolanthanide catalysts of the type [Me2Si(OHF)(CpR*)]LnN(TMS)2 (OHF ) η5-octahydrofluorenyl; Cp ) η5-C5H3; R* ) (-)-menthyl; Ln ) Sm, Y), and [Me2Si(η5-Me4C5)(CpR*)]SmN(TMS)2 (Cp ) η5-H3C5; R* ) (-)-menthyl) mediate asymmetric intramolecular hydroamination/cyclization of amines bearing internal olefins and afford chiral 2-substituted piperidine and pyrrolidine in enantioselectivities as high as 84:16 er at 60 °C. The substrate of the structure NH2CH2CMe2CH2CHdCH(CH2)2CHdCH2 is regiospecifically bicyclized by [Me2Si(η5-Me4C5)(tBuN)]LnE(TMS)2 to the corresponding indolizidine skeleton in good yield and high diastereoselectivity. Thermolysis of (η5-Me5C5)2LaCH(TMS)2 in cyclohexane-d12 at 120 °C rapidly releases CH2(SiMe3)2 and leads to possible formation of fulvene (η6-Me4C5CH2-) species. The thermolysis product readily reverts to active catalysts upon protonolysis by substrate and exhibits the same catalytic activity as the (η5,η1-Me5C5)2LaCH(TMS)2 precatalyst at 120 °C in the cyclization of cis-2,2-dimethylhept-5-enylamine. Catalytically-active lanthanide-amido complexes (η5-Me5C5)2La(NHR)(NH2R)n and [Me2Si(η5-Me4C5)(tBuN)]Sm(NHR)(NH2R)n are shown to be thermally robust species. Introduction Cyclizations of amine-tethered 1,2-disubstituted alkenes are of fundamental importance for the construction of heterocyclic systems bearing key substituents present in naturally occurring alkaloids. Although atom-efficient catalytic cyclohydroamination of amine-tethered unactivated 1,2-disubstituted olefins would be a synthetically valuable and straightforward approach for the construction of naturally occurring alkaloid skeletons, it has been a difficult process to achieve.1 Recently, substantial literature has emerged concerning the catalytic hydroamination of internal olefins activated by neighboring functional groups2 (e.g., conjugated dienes,3 vinylarenes,4 R,β-unsaturated ketones,5 R,β-unsaturated esters,6 R,βunsaturated nitro compounds, and acrylonitrile6,7) and †

Northwestern University. Emory University. (1) Mu¨ller, T. E.; Beller, M. Chem. Rev. 1998. 98, 675-703 and references therein. (2) Beller, M.; Breindl, C.; Eichberger, M.; Hartung, C. G.; Seayad, J.; Thiel, O. R.; Tillack, A.; Trauthwein, H. Synlett 2002, 10, 15791594 and references therein. ‡

mediated by a variety of metal ions (eq 1). Nonetheless,

only a few examples1,8 have been reported9 concerning the catalytic hydroamination of unactivated internal (3) (a) Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 3669-3679. (b) Hong, S.; Marks, T. J. J. Am. Chem. Soc., 2002, 124, 7886-1887. (c) Lo¨ber, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366-4367. (d) Minami, T.; Okamoto, H.; Ikeda, S.; Tanaka, R.; Ozawa, F.; Yoshifuji, M. Angew. Chem., Int. Ed. 2001, 40, 4501-4503. (4) Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1166-1167. (b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546-9547. (c) Beller, M.; Thiel, O. R.; Trauthwein, H.; Hartung, C. G. Chem. Eur. J. 2000, 6, 2513-2522. (5) Bozel, J. J.; Hegedus, L. S. J. Org. Chem. 1981, 46, 2561-2563. (6) Kawatsura, M.; Hartwig, J. F. Organometallics 2001, 20, 19601964. (7) Fadini, L.; Togni, A. Chem. Commun. 2003, 30-31. 10.1021/jo035417c CCC: $27.50 © 2004 American Chemical Society

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J. Org. Chem. 2004, 69, 1038-1052

Published on Web 01/21/2004

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes

olefins. N-H bond insertion across electron-rich, unactivated 1,2-disubstituted alkenes is impeded by a high enthalpic barrier, which likely reflects steric encumbrance as well as electrostatic repulsion between the nitrogen lone pair and the 1,2-disubstituted alkene π system.10 Catalytic approaches to this process11 involve either amine activation or olefin activation by early-12 or late-transition metals8,13 to reduce the electrostatic repulsion. In both cases, catalytic amine addition to unacti(8) (a) Rh-catalyzed hydroamination of norbornene: Brunet, J.-J.; Commenges, G.; Neibecker, D.; Philippot, K. J. Organomet. Chem. 1994, 469, 221-228. (b) Pd-catalyzed oxidative amination: Van Benthem, R. A. T. M.; Hiemstra, H.; Longarela, G. R.; Speckamp, W. N. Tetrahedron Lett. 1994, 35, 9281-9284. (c) Ir-catalyzed hydroamination of norbornene: Casalnuovo, A. L.; Calabrese, J. C.; Milstein, D. J. Am. Chem. Soc. 1988, 110, 6738-6744. (d) Ir-catalyzed asymmetric hydroamination of norbornene: Aufdenblatten, R.; Diezi, S.; Togni, A. Monatsh. Chem. 2000, 131, 1345-1350. Dorta, R.; Egli, P.; Zurcher, F.; Togni, A. J. Am. Chem. Soc. 1988, 119, 10857-10858. (e) For intramolecular hydroamination of tethered aminoalkenes using stoichiometric K2PtCl4, see: Ambuehl, J.; Pregosin, P. S.; Venanzi, L. M.; Ughetto, G.; Zambonelli, L. Angew. Chem., Int. Ed. Engl. 1975, 14, 369. (9) Long reaction times (3-12 days) and low to moderate chemical yields (5-50%) are observed for Ir and Rh. (10) Taube, R. In Applied Homogeneous Catalysis with Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.; VCH: Weinheim, 1996; Vol. 1, p 507. (11) For recent reviews of catalytic amine addition to C-C multiple bonds, see: (a) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104114. (b) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. Adv. Synth. Catal. 2002, 344, 795-813. (c) Molander, G. A.; Romero, J. A. C. Chem. Rev. 2002, 102, 2161-2185. (d) Pohlki, F.; Heutling, A.; Bytschkov, I.; Hotopp, T.; Doye, S. Synlett 2002, 5, 799-801. (e) Mu¨ller, T. E.; Beller, M. In Transition Metals for Organic Synthesis; Beller, M., Bolm C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 2, pp 316-330. (f) ref 1. (g) Roundhill, D. M. Catal. Today 1997, 37, 155-165. (h) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113-1126. (12) For hydroaminations mediated by early transition metals, see: (a) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003, 6, 935-946. (b) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003, 5, 586-587. (c) Cao, C.; Ciszewski, J. T.; Odom, A. L. Organometallics 2002, 21, 5148. (d) Tillack, A.; Castro, I. G.; Hartung, C. G.; Beller, M. Angew. Chem., Int. Ed. 2002, 41, 2541-2543. (e) Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853-2856. (f) Ackermann, L.; Bergman, R. G. Org. Lett. 2002, 4, 1475-1478. (g) Cao, C.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20, 5011-5013. (h) Shi, Y.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20, 3967-3969. (i) Straub, T.; Haskel, A.; Neyroud, T. G.; Kapon, M.; Botoshansky, M.; Eisen, M. S. Organometallics 2001, 20, 5017-5035. (j) Kim, Y. K.; Livinghouse, T.; Bercaw, J. E. Tetrahedron Lett. 2001, 42, 2933-2935. (k) Haak, E.; Siebeneicher, H.; Doye, S. Org. Lett. 2000, 2, 1935-1937. (l) Molander, G. A. Chemtracts: Org. Chem. 1998, 11, 237-263. (m) Haskel, A.; Straub, T.; Eisen, M. S. Organometallics 1996, 15, 3773-3775. (n) McGrane, P. L.; Livinghouse, T. J. Am. Chem. Soc. 1993, 115, 11485-11489. (o) Baranger, A. M.; Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc. 1993, 115, 2753-2763. (p) Walsh, P. J.; Hollander, F. J.; Bergman, R. G. Organometallics 1993, 12, 37053723. (q) McGrane, P. L.; Jensen, M.; Livinghouse, T. J. Am. Chem. Soc. 1992, 114, 5459-5460. (13) For hydroamination mediated by late transition metals, see: (a) Reference 3a,c. (b) Reference 4. (c) Reference 7. (d) Nakamura, I.; Bajracharya, G. B.; Yamamoto, Y. J. Org. Chem. 2003, 68, 2297-2299. (e) Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 1267012671. (e) Mueller, T. E.; Berger, M.; Grosche, M.; Herdtweck, E.; Schmidtchen, F. P. Organometallics 2001, 20, 4384-4393. (f) Kondo, T.; Okada, T.; Suzuki, T.; Mitsudo, T.-a. J. Organomet. Chem. 2001, 622, 149-154. (g) Vasen, D.; Salzer, A.; Gerhards, F.; Gais, H.-J.; Stuermer, R.; Bieler, N. H.; Togni, A. Organometallics 2000, 19, 539546. (h) Mu¨ller, T. E.; Pleier, A.-K. J. Chem. Soc., Dalton Trans. 1999, 583-587. (i) Beller, M.; Trauthwein, H.; Eichberger, M.; Breindl, C.; Herwig, J.; Muller, T. E.; Thiel, O. R. Chem. Eur. J. 1999, 5, 13061319. (j) Al-Masum, M.; Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1997, 38, 6071-6074. (k) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584-3585. (l) Besson, L.; Gore´, J.; Cazes, B. Tetrahedron Lett. 1995, 36, 3857-3860. (m) Seligson, A. L.; Trogler, W. C. Organometallics 1993, 12, 744-751. (n) Tamaru, Y.; Hojo, M.; Higashimura, H.; Yoshida, Z.-I. J. Am. Chem. Soc. 1988, 110, 3994-4002. (o) Armbruster, R. W.; Morgan, M. M.; Schmidt, J. L.; Lau, C. M.; Riley, R. M.; Zabrowski, D. L.; Dieck, H. A. Organometallics 1986, 5, 234-237. (p) Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc. 1982, 104, 2444-2451.

vated internal olefins is markedly sensitive to the steric encumbrance of the olefin substituents, leading to sluggish reaction rates and/or low yields. Organolanthanide-catalyzed heteroatom hydroelementation14-17 is an atom-economical and highly desirable process. The chemistry is defined by unique features of organolanthanide complexes:18 (i) highly electrophilic, kinetically labile f-element centers which are compatible with a variety of non-dissociable ancillary ligands, (ii) a generally single, thermodynamically stable oxidation state (Ln3+) reducing the complication introduced by competing oxidative addition/reductive elimination pathways, (iii) large possible coordination numbers (8-12) for which the metal ions are in most cases coordinatively unsaturated, (iv) 4fn orbitals shielded by filled 5s2 5p6 orbitals, which renders the chemistry of lanthanides highly ionic and governed more by electrostatic and steric factors than by orbital filling energetics. Furthermore, organolanthanide-catalyzed hydroamination is potentially one of the most efficient and elegant processes for the construction of naturally occurring alkaloid skeletons. Over the past decade, catalytic regio-/diastereo-/enantioselective intramolecular cyclohydroamination catalyzed by trivalent lanthanocene complexes18 has been extensively investigated. Major advances include cyclohydroaminations of aminoalkenes,19 aminoalkynes,20 aminoallenes,21 tandem bicyclizations of aminodienes, amino(14) Hydrogenation: (a) Obora, Y.; Ohta, T.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1997, 119, 3745-3755. (b) Roesky, P. W.; Denninger, U.; Stern, C. L.; Marks, T. J. Organometallics 1997, 16, 4486-4492. (c) Haar, C. M.; Stern, C. L.; Marks, T. J. Organometallics 1996, 15, 1765-1784. (15) Hydrosilylation: (a) Molander, G. A.; Corrette, C. P. Organometallics 1998, 17, 5504-5512. (b) Schumann, H.; Keitsch, M. R.; Winterfeld, J.; Muhle, S.; Molander, G. A. J. Organomet. Chem. 1998, 559, 181-190. (c) Fu, P.-F.; Brard, L.; Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1995, 117, 7157-7168. (d) Molander, G. A.; Julius, M. J. Org. Chem. 1992, 57, 6347-6351. (e) Sakakura, T.; Lautenschlager, H.; Tanaka, M. J. Chem. Soc., Chem. Commun. 1991, 40-41. (16) Hydroboration: (a) Molander, G. A.; Pfeiffer, D. Org. Lett. 2001, 3, 361-363. (b) Bijpost, E. A.; Duchateau, R.; Teuben, J. H. J. Mol. Catal. 1995, 95, 121-128. (c) Harrison, K. N.; Marks, T. J. J. Am. Chem. Soc. 1992, 114, 9220-9221. (17) Hydrophosphination: (a) Douglass, M. R.; Marks, T. J. J. Am. Chem. Soc. 2000, 122, 1824-1825. (b) Douglass, M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 2001, 123, 10221-10238. (18) For recent organolanthanide reviews, see: (a) Aspinall, H. C. Chem. Rev. 2002, 102, 1807-1850. (b) Edelmann, F. T.; Freckmann, D. M. M.; Schumann, H, Chem. Rev. 2002, 102, 1851-1896. (c) Arndt, S.; Okuda, J. Chem. Rev. 2002, 102, 1953-1976 (d) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187-2210. (e) Inanaga, J.; Furuno, H.; Hayano, T. Chem. Rev. 2002, 102, 2211-2226. (f) Molander, G. A. Chemtracts: Org. Chem. 1998, 18, 237-263. (g) Edelmann, F. T. Top. Curr. Chem. 1996, 179, 247-276. (h) Edelmann, F. T. In Comprehensive Organometallic Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon Press: Oxford, U.K., 1995; Vol. 4, Chapter 2. (i) Schumann, H.; Meese-Marktscheffel, J. A.; Esser, L. Chem. Rev. 1995, 95, 865-986. (j) Schaverien, C. J. Adv. Organomet. Chem. 1994, 36, 283-362. (k) Evans, W. J. Adv. Organomet. Chem. 1985, 24, 131-177. (l) Marks, T. J.; Ernst, R. D. In Comprehensive Organometallic Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon Press: Oxford, U.K., 1982; Chapter 21. (19) (a) Giardello, M. A.; Conticello, V. P.; Brard, L.; Gagne´, M. R.; Marks, T. J. J. Am. Chem. Soc. 1994, 116, 10241-10254. (b) Gagne´, M. R.; Marks, T. J. J. Am. Chem. Soc. 1992, 114, 275-294. (c) Gagne´, M. R.; Nolan, S. P.; Marks, T. J. Organometallics 1990, 9, 1716-1718. (d) Gagne´, M. R.; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 41084109. (20) (a) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 92959306. (b) Li, Y.; Fu, P.-F.; Marks, T. J. Organometallics 1994, 13, 439440. (21) (a) Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949-1960. (b) Arredondo, V. M.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 4871-4872.

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Ryu et al. SCHEME 1. Proposed Catalytic Cycle for Organolanthanide-Catalyzed Cyclohydroamination of Aminoalkenes

diynes, and aminoenynes,22 as well as recent application to the stereoselective synthesis of the bicyclic alkaloid, (+)-xenovenine.23 The mechanistically well-defined catalytic cycle19-23 for organolanthanide-catalyzed hydroamination (Scheme 1) demonstrates that after rapid and quantitative protonolysis of hydrocarbyl or amido precatalysts (Scheme 1, step i), insertion of C-C multiple bonds into Ln-N bonds via a four-centered transition state (T1, Scheme 1, step ii) can be efficaciously coupled to facile protonolysis of the resulting Ln-C bonds (Scheme 1, step iii). Thermodynamic considerations24,25 indicate that 1,2-disubstituted olefin insertion into a Ln-N bond (Scheme 1, step ii) is ∼6 kcal/mol more exothermic than for terminal olefins (∆H ≈ -6 kcal/mol for an internal olefin vs ∆H ≈ 0 kcal/mol for a terminal olefin), whereas the subsequent protonolysis (Scheme 1, step iii) is ∼6 kcal/mol less exothermic than for terminal olefins (∆H ≈ -7 kcal/mol for an internal olefin vs ∆H ≈ -13 kcal/ mol for a terminal olefin). The estimated overall ∆H for (22) (a) Hong, S.; Kawaoka, A. M.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 15878-15892. (b) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757-1771. (c) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 707-708. (23) Arredondo, V. A.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1999, 121, 3633-3639. (24) Metal-ligand bond enthalpies from: (a) Nolan, S. P.; Stern, D.; Hedden, D.; Marks, T. J. ACS Symp. Ser. 1990, No. 428, 159-174. (b) Nolan, S. P.; Stern, D.; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 7844-7853. (c) Schock, L. E.; Marks, T. J. J. Am. Chem. Soc. 1988, 110, 7701-7715. (d) Bruno, J. W.; Marks, T. J. J. Am. Chem. Soc. 1983, 105, 6824-6832. (25) Organic fragment bond enthalpies from: (a) Griller, D.; Kanabus-Kaminska, J. M.; Maccoll, A. J. Mol. Struct. 1988, 163, 125-131. (b) McMillan, D. F.; Golden, D. M. Annu. Rev. Phys. Chem. 1982, 33, 493-532 and references therein. (c) Benson, S. W. Thermochemical Kinetics, 2nd ed.; Wiley: New York, 1976; Appendix Tables A.10, A.11, A.22. (d) Benson, S. W. J. Chem. Educ. 1965, 42, 502-518.

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N-H addition to 1,2-disubstituted alkenes is therefore estimated to be similar to that for N-H addition to terminal alkenes. The feasibility of Ln-N addition to RHCdCHR′ functionalities is supported by the fact that the estimated ∆H value of turnover-limiting Ln-N addition to RHCdCHR′ is more exothermic than that of Ln-N addition to RHCd CH2. However, published observations21a,26 clearly indicate that Ln-N bond addition to RHCdCHR′ is hampered by a higher kinetic barrier than Ln-N bond insertion into RHCdCH2. This inherent limitation21a,26 in organolanthanide-catalyzed 1,2-disubstituted alkene insertion is, as noted above, reasonably attributed to severe nonbonded repulsions and possible charge separation imbalance in the reasonably well-characterized transition state19b (T1, Scheme 1), both deriving from the sterically demanding, electron-donating alkyl substitution. The steric sensitivity of the olefin insertion step also doubtless reflects subtle changes in the catalyst coordination environment, and therefore, lanthanide ions of maximum ionic radius and more open ancillary ligation should in principle reduce the congestion.19b Indeed, a preliminary investigation revealed that organolanthanidecatalyzed cyclohydroamination of aminoalkenes bearing 1,2-disubstituted olefins can be a viable process with appropriate catalyst and reaction conditions.27 However, these observations also raise questions about scope and mechanism vis-a`-vis more conventional hydroaminations. Herein we report a full discussion of the use of more coordinatively unsaturated and thermally robust organolanthanide precatalysts combined with higher reaction temperatures to extend aminoalkene cyclohydroaminations to 1,2-disubstituted alkenes. In addition, a full account of reaction scope, diastereo- and enantioselectivity, metal and ancillary ligand effects, reaction kinetics, and the thermal stability of the precatalysts and catalytically active species are presented. Results The principal goal of this study was to address a significant current limitation of aminoalkene hydroamination and to explore in detail the scope and selectivity of the organolanthanide-catalyzed intramolecular hydroamination/cyclization of amine-tethered, sterically hindered 1,2-disubstituted alkenes. This section focuses on the generation of catalytically active species derived from organolanthanide precatalysts, the scope of the cyclization reactions in terms of ring size and substitution pattern, and the selectivity, including diastereoselectivity and enantioselectivity. Next, variation of catalyst turnover frequency with metal ion size and ancillary ligation is described, followed by analysis of reaction kinetics and rate law. Finally, the thermal stability of the precatalysts and catalytically active species at the rather high reaction temperatures employed are discussed. Organolanthanide Precatalysts for Hydroamination of 1,2-Disubstituted Alkenes and Catalyst Gen(26) Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1998, 63, 89838988. (27) (a) Ryu, J.-S.; Marks, T. J.; McDonald, F. E. Org. Lett. 2001, 3, 3091-3094. (b) Ryu, J.; Marks, T. J.; McDonald, F. E. Presented in part at the 221st National meeting of the American Chemical Society, San Diego, CA, April 1-5, 2001; American Chemical Society: Washington, DC, 2001; Abstract ORGN 265.

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes

FIGURE 1. Organolanthanide precatalysts for hydroamination of 1,2-disubstituted alkenes.

eration. Figure 1 depicts the organolanthanide precatalysts which were used in the present study. A selected variety of substrates have been screened using achiral catalysts (5-7) and C1-symmetric chiral catalysts (8 and 9). Achiral precatalysts 5, 6, and 7 have different degrees of coordinative unsaturation, which are characterized by their “bite” angles (ring centroid-Ln-ring centroid), of ∼134°,28 ∼122 °,29 and ∼101°,30 respectively. The present study shows that all of these precatalysts, with the exception of sterically congested 5c, efficiently mediate the cyclization of amines bearing 1,2-disubstituted internal olefins at 60-125 °C. When the reaction is carried out at 60 °C, impractically long reaction times are observed (e.g., for 16 f 17 mediated by 8b, Nt ) 0.03 h-1), while reaction at temperatures higher than 135 °C lead to unassignable peaks in the 1H NMR. Routes into the catalytic cycle are well-established for amino-olefin hydroamination.19b Amine precoordination to the lanthanide metal leads to essentially instantaneous protonolysis of the precatalyst Ln-C or Ln-N bond via a four-centered transition state19b,31 to afford a catalytically-active organolanthanide amine-amido complex, Cp′2Ln(NHR)(NH2R)n, and the corresponding H2C(SiMe3)2 or HN(SiMe3)2 products. In the present studies, rapid and quantitative protonolysis of the Ln-E σ bond with concomitant formation of H2C(SiMe3)2 is observed within seconds by 1H NMR for most substrates and catalysts at 125 °C.19-23 However, when sterically congested precatalysts such as 8b are employed, precatalyst (28) Jeske, G.; Lauke, H.; Mauermann, H.; Swepston, P. N.; Schumann, H.; Marks, T. J. J. Am. Chem. Soc. 1985, 107, 8091-8103. (29) (a) Jeske, G.; Schock, L. E.; Mauermann, H.; Swepston, P. N.; Schumann, H.; Marks, T. J. J. Am. Chem. Soc. 1985, 107, 8103-8110. (b) Stern, D.; Sabat, M.; Marks, T. J. J. Am. Chem. Soc. 1990, 112, 9558-9575. (30) Tian, S.; Arredondo, V. M.; Stern, C. L.; Marks, T. J. Organometallics 1999, 18, 2568-2570. (31) M-C/M-H bond cleavage via a four-centered transition state: (a) Piers, W. E.; Shapiro, P. J.; Bunel, E. E.; Bercaw, J. E. Synlett 1990, 74-84. (b) Thompson, M. E.; Baxter, S. M.; Bulls, A. R.; Burger, B. J.; Nolan, M. C.; Santarsiero, B. D.; Schaefer, W. P.; Bercaw, J. E. J. Am. Chem. Soc. 1987, 109, 203-219. (c) Doherty, N. M.; Bercaw, J. E. J. Am. Chem. Soc. 1985, 107, 2670-2682.

1 H NMR monitoring of the cyclization 16 f 17 mediated by 7a: (A) 0.01 h, (B) 7 h, (C) 21 h, (D) 33 h, (E) 90 h, (F) 139 h.

FIGURE 2.

peaks are observed initially, and Ln-C/Ln-N protonolysis requires several minutes. These differences in protonolysis rates likely reflect the relative ease of amine precoordination proximate to the sterically congested Ln-C/Ln-N bond. This is supported by the observation that, by 1H NMR, no precatalyst peaks are observed in the case of sterically more open precatalysts in the presence of less hindered amines, whereas sterically congested precatalysts and sterically encumbered amines32 exhibit relatively long (several minutes) induction periods. Scope of Intramolecular Hydroamination/Cyclization of Amine-Tethered 1,2-Disubstituted Alkenes. The organolanthanide complexes Cp′2LnR (5), Me2SiCp′′2SmR (6), (CGC)LnR (7), Me2Si(OHF)(CpR*)LnR (8), and Me2SiCp′′(CpR*)SmR (9) (Cp′) η5-Me5C5; Cp′′ ) η5-Me4C5; Cp ) η5-H3C5; R* ) (-)-menthyl; R ) CH(SiMe3)2, N(SiMe2)3; Figure 1) serve as effective pre(32) A substrate bearing an R-methyl substituent such as 2-aminohept-5-ene (18) exhibits a relatively long induction period.

J. Org. Chem, Vol. 69, No. 4, 2004 1041

Ryu et al. TABLE 1. Organolanthanide-Catalyzed Intramolecular Hydroamination/Cyclization of Amines Tethered to Unactivated 1,2-Disubstituted Alkenesa

a Conditions: All reactions conducted with 5 mol % precatalyst in o-xylene-d b 10 at 125 °C (unless otherwise indicated). Determined in o-xylene-d10. c Determined by 1H NMR spectroscopy and GC-MS. d Isolated yield in NMR-scale reaction. e Isolated yield of the corresponding HCl salt in preparative-scale reaction; the reactions were conducted in C6H6. f 10 mol % of precatalysts was employed. g Turnover frequency (N ) could not be accurately determined by NMR due to paramagnetism; reactions were quenched after 36 h (10 f t 11), 5 d (16 f 17), 48 h (18 f 19), and 2 d (20 f 21). h Cis/trans ) 81:19 ratio observed by 1H NMR spectroscopy and GC-MS. Isolation yield of the free amine.

catalysts for clean and in most cases quantitative intramolecular hydroamination/cyclization of amine-tethered 1,2-disubstituted alkenes to yield the corresponding pyrrolidines, piperidines, and indolizidines as shown in Table 1, where Nt is the catalytic turnover frequency at the temperature indicated. In general, the catalytic hydroamination/cyclization reactions of amine-tethered 1,2-disubstituted alkenes proceed to completion at 120125 °C under inert atmosphere, at 5 mol % catalyst loading in 1 h to 3 days. Reaction progress is conveniently monitored from intensity changes in substrate olefinic resonances by 1H NMR spectroscopy, using evolved (Scheme 1) HN(SiMe3)2 or H2C(SiMe3)2 as convenient internal NMR standards (e.g., Figure 2).19-23 All reactions were carried out in noncoordinating hydrocarbon solvents such as benzene-d6, toluene-d8, or o-xylene-d10, and no significant solvent effects are observed. Turnover frequencies were determined in o-xylene-d10 at 125 °C from the slope of the kinetic plots of substrate: catalyst ratio vs time. In general, substantial line broadening of primary amine substrate resonances is observed in the presence of paramagnetic orgnolanthanide catalysts such 1042 J. Org. Chem., Vol. 69, No. 4, 2004

as those of Sm(III) and Yb(III). However, negligible line broadening is observed for sterically bulky piperidine or pyrrolidine (secondary amine) products through the course of the reactions. This observation indicates rapid exchange of bound amine and presumably amido groups with free substrate, and little competitive product binding. Preparative-scale reactions were carried out in sealed reaction tubes at 120-125 °C. The final pyrrolidine, piperidine, and indolizidine products were vacuum transferred with other volatiles and then treated with anhydrous HCl in ether. The resulting hydrochloride salts were purified by recrystallization. The final hydroamination/cyclization products were characterized by 1H, 13C, 2D-NMR spectroscopy, GC/MS, high-resolution MS, and elemental analysis. The present high-temperature hydroamination/cyclization process for amine-tethered 1,2-disubstituted alkenes is effective in catalytic transformations to form 2-alkylsubstituted piperidines, pyrrolidines, 2,5-disubstituted pyrrolidines, and indolizidines. The present study reveals that thermally stable and reactive bis-cyclopentadienyl precatalysts such as Cp′2LaCH(SiMe3)2 (5a) and

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes

Me2SiCp′′2SmCH(SiMe3)2 (6a) are the most effective precatalysts for less hindered aminoalkene substrates (Table 1, entries 1-4). In contrast, ansa-mono-Cp “contained geometry” precatalysts having more open coordination environments and high thermal stability such as (CGC)LnE(SiMe3)2 (7a-d) are the most effective precatalysts for sterically hindered aminoalkene substrates bearing R-methyl substituents (Table 1, entries 5). All other factors being equal, the most likely electronic effect of bis-Cp ligation33 would be to enhance the lanthanidecentered hydroamination activity over that of CGCligation unless pronounced steric factors are involved. Substrate ring size effects for cyclohydroamination of the present internal olefin are analogous to those observed in other organolanthanide-mediated hydroaminations; in general, increased product ring size correlates with decreased Nt (5 > 6 > 7) in cyclohydroamination of aminoalkenes,19 aminoalkynes,20 and aminoallenes.21 An exception is the transformation of 16 f 17 mediated by Cp′2La-, which does not follow the ring size trend of 5 > 6. Transformation 12 f 13 (Table 1) illustrates that cyclization is not restricted to methyl-substituted olefins. The present catalytic process is also applicable to aminoalkenes bearing a longer alkyl substituent. Thus, transformation 20 f 21 illustrates the feasibility of scope extension to longer alkyl substituents as well as tandem bicyclization. When (CGC)YbCH(TMS)2 is employed for the cyclization of aminodiene 20 at 125 °C, regiospecific CdC bond insertion of the internal olefin into the Ln-N bond is effectively coupled to diastereoselective CdC bond insertion of the pendent terminal olefin into the Ln-N bond of a pyrrolidinido intermediate, after rapid protonolysis of the Ln-C bond (eq 2). Entry 6 in Table 1 also

reveals that direct insertion of the terminal CdC functionality into the Ln-C bond does not compete with amine protonolysis, presumably reflecting, among other factors, the unfavorable strain energy associated with the formation of a four-membered ring. During the course of reaction, intermediate pyrrolidine A is observable by 1H NMR spectroscopy. (33) For examples where electron-donating metallocene ligands exhibit higher activities in olefin polymerization, see: (a) Ewen, J. A.; Elder, M. J.; Jones, R. L.; Rheingold, A. L.; Liable-Sands, L. M.; Sommer, R. D. J. Am. Chem. Soc. 2001, 123, 4763-4773. (b) Klosin, J.; Kruper, W. J., Jr.; Nickias, P. N.; Roof, G. R.; Waele, P. D.; Abboud, K. A. Organometallics 2001, 20, 2663-2665. (c) Ewen, J. A.; Jones, R. L.; Elder, M. J.; Rheingold, A. L.; Liable-Sands, L. M. J. Am. Chem. Soc. 1998, 120, 10786-10787.

TABLE 2. Diastereoselectivities in the Intramolecular Hydroamination/Cyclization of trans-2-Aminohept-5-ene (18)

entry

precatalysts

Nt

1 2 3 4

(CGC)SmN(TMS)2 (7a) (CGC)YN(TMS)2 (7b) (CGC)YbCH(TMS)2 (7c) (CGC)LuCH(TMS)2 (7d)

0.41 0.23 b 0.23

trans/cisa conversion (%) 11:1 16:1 15:1 15:1

95 90 91 77

a Determined by 1H NMR spectroscopy and GC-MS. b Turnover frequency (Nt) could not be accurately determined by NMR due to paramagnetism.

Geminal dimethyl substitution on the tether is not required in five-membered ring closure (Table 1, entries 1-3 and 5). However, six-membered ring closure is sluggish without assistance from the Thorpe-Ingold effect (entry 4).34 An attempt was also made to effect cyclization of aminohept-5-ene (B) to the corresponding piperidine. However, less than 15% conversion is observed at 125°C over a period of 5 days when using Cp′2LaCH(SiMe3)2.

Reaction Selectivity. In principle, cyclization of aminoheptene 18 could afford a mixture of trans- and cis2-ethyl-5-methylpyrrolidines (19). Table 2 shows the product isomer ratios obtained using a variety of (CGC)LnE(SiMe3)2 (7a-d) precatalysts. The ratios are invariant with conversion and do not change after completion of the reaction (i.e., ring closure is essentially irreversible). The (CGC)Ln- catalytic system demonstrates superior diastereoselectivity in the cyclohydroamination of 22 than the Cp′2Ln-, Me2SiCp′′2Ln-, and Et2SiCp′′CpLn- systems (eq 3). Thus, the Cp′2Sm-, Me2-

SiCp′′2Sm-, and (CGC)Sm- catalysts provide product trans/cis ratios of 1:1.25,19b 1:1,19b and 10:1,30 respectively. The present cyclohydroamination of the more sterically encumbered trans-2-aminohept-5-ene (18) mediated by (CGC)Ln- catalysts is comparable in diastereoselectivity to those of 2-aminohex-5-ene (22) even at 120 °C (Table 1, entry 5) and the diastereoselectivity is not sensitive to temperature. In addition, the diastereoselectivity of trans-2-aminohept-5-ene (18) ring closures are found to be rather insensitive to lanthanide ion size (Table 2), which is in marked contrast to the 22 f 23 cyclization mediated by Cp′2LnR, Me2SiCp′′2LnR, and Et2SiCp′′CpLnR catalysts.35 The major product trans disubstituted pyr(34) Kirby, A. J. Adv. Phys. Org. Chem. 1980, 17, 183-278. (35) The diastereoselectivities of cyclization 22 f 23 mediated by the (CGC)Ln- catalyst system were relatively insensitive to Ln ion size,30 while those of an analogous phosphinoalkene ring closure mediated by Cp′2LnR catalysts is highly dependent on Ln ion size.17b

J. Org. Chem, Vol. 69, No. 4, 2004 1043

Ryu et al. TABLE 3. Enantioselectivities in the Intramolecular Hydroamination/Cyclization of Substrates 10, 12, and 16 Catalyzed by C1-Symmetric Chiral Catalysts 8 and 9a

a Conditions: All reactions conducted with 5 mol % precatalyst in C D (unless otherwise indicated). R* ) (-)-menthyl. b The reaction 6 6 was carried out in o-xylene-d10. c The reactions were conducted with 20 mol % precatalyst in C6D6.

rolidine configuration is assigned by 2D-NOESY spectroscopy. Presumably, trans selectivity depends on steric/ conformational effects in the (CGC)Ln-amido transition state. A possible mechanistic pathway is considered in the Discussion. The chiral organolanthanide precatalysts Me2Si(OHF)(CpR*)LnN(TMS)236 and Me2SiCp′′(CpR*)SmN(TMS)237 (Figure 1, catalysts 8 and 9) are partially effective in the asymmetric cyclohydroamination of amine-tethered 1,2disubstituted alkenes (Table 3) at 80-100 °C. It was found that 2,2-dimethylhex-4-enylamine (10) and 2,2dimethyl-hept-4-enylamine (12) undergo sluggish cyclization in the presence of Me2Si(OHF)(CpR*)YN(TMS)2 (8b) at 80 °C; therefore, reactions were carried out at 100 °C. However, it is also found that 2,2-dimethylaminohept5-ene (16) undergoes rapid cyclization in the presence of Me2Si(OHF)(CpR*)YN(TMS)2 (8b) at 100 °C and even at 60 °C. The rapid cyclization in the six-membered ring closure exhibits a deviation from the 5 > 6 trend generally observed in terminal amino-olefin hydroamination/cyclizations.17-19 As might be expected, turnover frequencies observed with the Me2SiCp′′(CpR*)Sm- catalyst (9a) are significantly greater than those observed with the Me2Si(OHF)(CpR*)Sm- catalyst (8a). Presumably the less sterically encumbered Me2SiCp′′(CpR*) ligand system provides a more open sphere for olefin coordination than the Me2Si(OHF)(CpR*) ligand system having the bulky octahydrofluorenyl “roof”, but in some cases, less stereodirecting capacity. Enantioselectivities of the asymmetric reactions were determined by chiral (36) Douglass, M. R.; Ogasawara, M.; Hong, S.; Metz, M. V.; Marks, T. J. Organometallics 2002, 21, 283-292. (37) (a) Haar, C. M.; Stern, C. L.; Marks, T. J. Organometallics 1996, 15, 1765-1784. (b) Giardello, M. A.; Conticello, V. P.; Brard, L.; Gagne, M. R.; Marks, T. J. J. Am. Chem. Soc. 1994, 116, 10241-10254. (c) Giardello, M. A.; Conticello, V. P.; Brard, L.; Sabat, M.; Rheingold, A. L.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1994, 116, 1021210240. (d) Gagne, M. R.; Brard, L.; Conticello, V. P.; Giardello, M. A.; Stern, C. L.; Marks, T. J. Organometallics 1992, 11, 2003-2005. (d) Conticello, V. P.; Brard, L.; Giardello, M. A.; Tsuji, Y.; Sabat, M.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1992, 114, 2761-2762.

1044 J. Org. Chem., Vol. 69, No. 4, 2004

HPLC analysis of 1-naphthoyl amie derivatives of the pyrrolidine and piperidine products.38 The amine-amido complexes of chiral C1-symmetric organolanthanide catalysts are known to undergo epimerization under catalytic hydroamination conditions to afford mixtures of (R)- and (S)-configurational isomers (e.g., eq 4). For the (-)-menthyl Me2SiCp′′(CpR*)Ln-

complexes, a 95:5 S/R equilibrium epimer ratio is established in the presence of a 40-50-fold excess of npropylamine within 2 hours at 25 °C.37b,c In the presence of a 200-fold excess of n-propylamine, the (-)-menthyl (S)-Me2Si(OHF)(CpR*)Y complex establishes a 70:30 S/R equilibrium ratio in ∼3 h at 25 °C.36 The equilibrium constant (K) and rate of the epimerization depend on the structure of the amine substrate, reaction temperature, catalyst, and amine concentration. In the present study, epimerization of diamagnetic (S)-Me2Si(OHF)(CpR*)Y in the presence of n-propylamine at an elevated reaction temperature (80 °C) was monitored from intensity changes in Cp resonance by 1H NMR spectroscopy. In the presence (38) For an example of the separation of 2-substituted piperidines, see: Hyun, M. H.; Jin, J. S.; Lee, W. Bull. Korean Chem. Soc. 1997, 18, 336-339.

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes

FIGURE 3. (A) Plot of normalized ratio of (S)-Me2Si(OHF)(CpR*)Y(NHnPr)(NH2nPr)n concentration to (R)-Me2Si(OHF)(CpR*)Y(NHnPr)(NH2nPr)n concentration in the presence of 20fold excess n-propylamine in o-xylene-d10 at 80 °C as a function of time. (B) Plot of normalized ratio of (S)-Me2Si(OHF)(CpR*)Y(NHR)(NH2R)n concentration to (R)-Me2Si(OHF)(CpR*)Y(NHR)(NH2R)n concentration in the presence of 20-fold excess 16 in o-xylene-d10 at 100 °C as a function of time.

of a 20-fold excess of n-propylamine,39 (S)-Me2Si(OHF)(CpR*)Y- is rapidly isomerized at 80 °C within 1 h to produce a mixture of (S)- and (R)-complexes (Figure 3A). The observed equilibrium constant is 0.64 (80 °C), which is higher than that at room temperature (∼0.43). As mentioned before, the equilibrium constant is highly dependent on substrate structure. For substrates 10, 12, and 16, equilibrium constants of 0.23 (100 °C), 0.43 (100 °C), and 0.32 (100 °C), respectively, are observed with 5 mol % (S)-Me2Si(OHF)(CpR*)Y- catalyst loadings after 2-3 days at 100 °C (Figure 3B). Presumably, aminoalkenes bearing a longer tether may have more difficulty in accessing the sterically congested Ln center than a more compact amine such as n-propylamine. Thus, bulky amines such as 10, 12, and 16 exhibit slower epimerization rates than a compact n-propylamine. Furthermore, this particular epimerization process is competitive with the catalytic hydroamination reaction. Cyclization 16 f 17 mediated by (S)-Me2Si(OHF)(CpR*)Y exhibits a relatively rapid reaction rate compared to 10 f 11 and 12 f 13 and an improved product denantiomer ratio is observed vs those of 10 and 12 (Table 3). The cyclization rate of 16 f 17 is comparable to the epimerization rate. Therefore, higher catalyst loadings and lower reaction temperatures in cyclization 16 f 17 efficiently suppress catalyst epimerization. When 20 mol % of (S)-Me2Si(OHF)(CpR*)Y is employed at 80 °C, (R)-Me2Si(OHF)(CpR*)Y-, which results from Ln-CpR* protonolysis, is not observed until the reaction is complete (Figure 4B; the Cp resonances of the (R) isomer appear at δ 6.15 ppm, (39) In this study, generally 5 mol % of chiral catalysts were employed in asymmetric hydroamination/cyclization. Thus, a 20-fold excess propylamine was employed to achieve consistent results.

FIGURE 4. (A) 500 MHz 1H NMR spectra of the Cp region of the mixture of the precatalyst 8b and a 20-fold excess of substrate 10 in o-xylene-d10 at 100 °C: (a) 0.01 h, (b) 5.4 h, (c) 20.7 h. (B) 500 MHz 1H NMR spectra of the Cp region of the mixture of the precatalyst 8b and 5-fold excess of substrate 16 in benzene-d6 at 80 °C: (a) 0.01 h, (b) 10.5 h, (c) 42.5 h.

5.92 ppm, and 5.60 ppm at 100 °C with 5 mol % catalyst after 50 h), and an improved enantiomer ratio (21:79 f 18:82) is observed (Table 3, entry 3). Lowering the reaction temperature to 60 °C leads to a slower reaction rate (Nt ) 0.03) with a slightly improved er (16:84). Metal and Ligand Effects on the Catalytic Process. In principle, the steric sensitivity of the turnoverlimiting olefin insertion step reflects subtle changes in the catalyst coordination environment. In fact, organolanthanide-catalyzed cyclohydroamination processes exhibit distinctive trends in turnover frequency with metal ionic radius; increasing the Ln3+ ionic radius from the smallest eight-coordinate ionic radius,40 Lu3+, to the largest, La3+, leads to increased turnover frequencies (Nt) for aminoalkenes,19 and decreased turnover frequencies for aminoalkynes.20 For aminoallenes21 the maximum Nt is observed using Y3+sa mid-sized Ln3+ ion. The present cyclohydroamination results for amine-tethered 1,2-disubstituted alkenes exhibit a trend similar to that of aminoalkenes; Cp′2Ln-catalyzed cyclohydroamination of 10 f 11 exhibits an increase in turnover frequency in proceeding from the smallest Y3+ (1.016 Å), to intermedi(40) (a) Representative eight-coordinate effective ionic radii: La(III), 1.160 Å; Nd(III), 1.109 Å; Sm(III), 1.079 Å; Y(III), 1.019 Å; Yb(III), 0.985 Å; Lu(III), 0.977 Å. (b) Shannon, R. D. Acta Crystallogr., Sect. A 1976, A32, 751-767.

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Ryu et al. TABLE 4. Lanthanide Ion Size Effects on the Turnover

TABLE 5. Ancillary Ligation Effect on the Turnover

Frequencies for Cyclohydroamination of Amines Tethered to Unactivated 1,2-Disubstituted Alkenes

Frequency for Cyclohydroamination of Amines Tethered to Unactivated 1,2-Disubstituted Alkenes

a Eight-coordinate ionic radii. b All rates measured in o-xylened10 at 125 °C with 5 mol % of precatalyst.

a Angle between centroid-Ln-centroid from refs 29-31. b All rates were measured in o-xylene-d10 at 125 °C with 5 mol % of precatalyst.

ate Sm3+ (1.079 Å), and to the largest La3+ (1.160 Å) spanning over 3 orders of magnitude (Table 4, entries 1-3). Under identical reaction conditions, a similar trend is observed for the transformation 16 f 17 (Table 4, entries 4-6). Presumably, lanthanide ions of maximum ionic radius reduce congestion in the turnover-limiting insertion step (Scheme 1, step ii) for sterically demanding 1,2-disubstituted alkenes. With regard to ancillary ligation effects, in parallel to the case of amine-tethered terminal olefins,19 low catalytic activity for cyclohydroamination of amine-tethered 1,2-disubstituted alkenes is observed with the coordinatively saturated Cp′2Sm- catalyst (Table 5, entries 1 and 4). The Me2SiCp′′2 ligand system, which provides a more open coordination sphere, dramatically increases the rates for cyclizations 10 f 11 and 16 f 17 (Table 5, entries 2 and 5). Kinetic data (see further discussion below) using both ligands clearly show zero-order kinetics in substrate concentration over three half-lives, i.e., the rate law is the same for the different ancillary ligands. Interestingly, cyclohydroamination of 1,2-disubstituted alkenes exhibits a markedly different trend with CGC complexes (Table 5, entries 3 and 6). Although the (CGC)Ln- complexes offer more open coordination environments than Cp′2Lncomplexes and exhibit enhanced reactivity for cyclohydroamintion of amine-tethered terminal olefins, they curiously exhibit relatively low reactivity for substrates 10 and 16 compared to the Me2SiCp′′2Ln- system. Replacing the strongly electron-donating Cp′ ligation with the less electron-donating amido ligation decreases reactivity (electronic effect).33 On the other hand, opening the coordination environment with respect to sterically demanding 1,2-disubstituted alkenes by removing a bulky Cp′ ligand enhances the reactivity (steric effect). 1046 J. Org. Chem., Vol. 69, No. 4, 2004

The competition between these effects makes activity and ancillary ligation correlations less clear-cut than in the case of less hindered R-olefinic substrates.19 Kinetic Studies of Hydroamination/Cyclization of Amine-Tethered 1,2-Disubstituted Alkenes. Quantitative kinetic studies of the cyclization of 1,2-disubstituted alkene-tethered amines were carried out with 5 mol % of precatalysts 5-9 in o-xylene-d10 at 125 °C. The diminution in the olefinic resonances (δ ∼ 5.4 ppm) was monitored by 1H NMR spectroscopy and integrated versus CH2(SiMe3)2 or NH(SiMe3)2 (δ ∼0.2 ppm) which are stoichiometrically generated upon substrate addition (Figure 2). Representative kinetic plots are shown in Figure 5. The linear decrease of olefin concentration with conversion (Figure 5A) suggests zero-order dependence on substrate concentration in analogy to the cyclohydroamination of less hindered aminoalkenes. However, when a (CGC)Sm- complex is employed, a pronounced deviation from linearity is observed after the first half-life (Figure 5B). This distinctive deviation from linearity is observed with all (CGC)Ln- catalysts, regardless of substrate structure and reaction time, and suggests competitive inhibition by product.19b,17b Since all substrates exhibit the same trend regardless of reaction time until the complete consumption of substrate, no catalyst decomposition is evident (see the discussion on the thermal stability of catalysts for details). Variable-temperature kinetic studies were conducted by in situ 1H NMR on transformation 10 f 11 mediated by Me2SiCp′′2Sm-. Data are shown in Figure 6A normalized to the CH2(TMS)2 internal standard. The cyclization rate for 10 f 11 mediated by Me2SiCp′′2Sm- is independent of substrate concentration over a 30 °C temper-

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes

FIGURE 7. Thermolysis rate data for organolanthanide precatalysts at 120 °C: (a) 10.7 mM (CGC)YN(TMS)2 solution in C6D12 with Cp2Fe as an internal calibration standard (2); (b) 16.8 mM Cp′2LaCH(TMS)2 solution in C6D12 with Cp2Fe as an internal calibration standard (9).

FIGURE 5. Ratio of substrate 10: lanthanide complex concentration as a function of time at 125 °C. (A) Transformation 10 f 11 mediated by 5 mol % Cp′2La- catalyst. The line is least-squares fit to the data points over three half-lives. (B) Transformation 10 f 11 mediated by 5 mol % (CGC)Smcatalyst. The line is least-squares fit to the data points for the first half-life (linear part).

FIGURE 6. (A) Normalized ratio of substrate 10: lanthanide concentration as a function of time and temperature for the cyclohydroamination of 2,2-dimethylaminohex-4-ene (10 f 11) using precatalyst Me2SiCp′′2SmCH(TMS)2 in o-xylene-d10. (B) Eyring plot for the cyclohydroamination of 2,2-dimethylaminohex-4-ene (10 f 11) using precatalyst Me2SiCp′′2SmCH(TMS)2 in o-xylene-d10. The line is the least-squares fit to the data points.

ature range (95-125 °C), suggesting zero-order behavior in substrate. Standard Eyring and Arrhenius kinetic

analyses41 yield activation parameters ∆Hq ) 17.7 (2.1) kcal/mol, ∆Sq ) -24.7 (5.0) eu, and Ea ) 18.5 (2.0) kcal/ mol.42 Precatalyst Thermal Stability. In the present study, all catalytic reactions are carried out at 120-125 °C, and this argues for appreciable catalyst thermal stability at high temperatures. Therefore, efforts to investigate the thermal stability of the precatalysts and catalyticallyactive species were made. The intrinsic thermal stability of the diamagnetic precatalysts Cp′2LaCH(TMS)2 and (CGC)YN(TMS)2 was scrutinized in C6D12 solution with each offering advantages: (i) diamagnetic Y3+ and La3+ allow convenient NMR monitoring of reaction without severe line broadening effects; (ii) Cp′2La- is the most frequently used precatalyst in the cyclization reaction due to its high reactivity; (iii) (CGC)Y- provides information on ansa-single ring complexes. The concentration of diamagnetic precatalyst vs time profiles depicted in Figure 7 illustrate approximately zero-order behavior in [precatalyst]. The thermal decomposition rate of (CGC)YN(TMS)2 is clearly very slow at 120 °C, while precatalyst Cp′2LaCH(TMS)2 decomposes rapidly. The diminution of precatalyst Cp′ resonances at δ 2.015 and 1.972 ppm, and the quantitative evolution of CH2(TMS)2 resonances at δ 0.030 and -0.268 ppm are observed by 1H NMR. The zero-order kinetic behavior and relatively rapid decomposition profile of the Cp′2La-hydrocarbyl precursor suggests an intramolecular thermolytic pathway, likely involving ring hydrogen C-H activating metalation by the large ionic radius metal La3+ and η5,η1Me4C5CH2- formation (eq 5).43 Any attempts to identify the thermolysis products were unsuccessful due to the high reactivity and instability of the products. NMR spectra were not structurally diagnostic because of overlapping resonances in the Cp region. On the other hand, it has been reported that Cp′2CeCH(TMS)2 decomposes via intramolecular C-H activation and reacts further to form a thermodynamically stable tetranuclear (41) (a) Robinson, P. J. J. Chem. Educ. 1978, 55, 509-510. (b) Benson, S. W. Thermochemical Kinetics, 2nd ed.; Wiley: New York, 1986; pp 8-10. (42) Parameters in parentheses represent 3σ values derived from the least-squares fit.

J. Org. Chem, Vol. 69, No. 4, 2004 1047

Ryu et al.

complex E which was characterized by X-ray crystallography.43d A similar decomposition route can be envisioned for Cp′2LaCH(TMS)2.

FIGURE 8. 400 MHz 1H NMR spectra of (CGC)Sm(NHnPr)-

To test the possible catalytic activity of the thermolysis products, cyclohydroamination of 16 was carried out in the presence of the Cp′2LaCH(TMS)2 thermolysis product. After clean and complete evolution of CH2(TMS)2 was observed at 120 °C in C6D12, an aliquot of 16 was added to the reaction mixture. Substrate addition leads to an instantaneous color change44 from dark red to colorless, suggestive of a lanthanide amine-amido complex, Cp′2La(NHR)(NH2R)n. Interestingly, the Cp′2LaCH(TMS)2 thermolysis product mediates the cyclohydroamination of 16 f 17 at a rate indistinguishable from that of Cp′2LaCH(TMS)2; Nt’s are 3.6 h-1 (120 °C) and 3.5 h-1 (120 °C) for Cp′2LaCH(TMS)2 and the thermolysis product, respectively. Thus, it appears that of any η5,η1-Me4C5CH2- species43 readily revert to the active catalyst upon protonolysis by amine substrates (eq 6). Clearly, precatalyst thermolysis does not adversely affect the activity of the catalytically active species.

(43) (a) Riley, P. N.; Parker, J. R.; Fanwick, P. E.; Rothwell, I. P. Organometallics 1999, 18, 3579-3583. (b) Sun, Y.; Spence, R. E. v. H.; Piers, W. E.; Parvez, M.; Yap, G. P. A. J. Am. Chem. Soc. 1997, 119, 5132-5143. (c) Brunner, H.; Wachter, J. Organometallics 1996, 15, 1327-1330. (d) Booij, M.; Meetsma, A.; Teuben, J. H. Organometallics 1991, 10, 3246-3252. (e) Schock, L. E.; Marks, T. J. J. Am. Chem. Soc. 1988, 110, 7701-7715. (f) Schock, L. E.; Brock, C. P.; Marks, T. J. Organometallics 1987, 6, 1219-1226. (g) Bulls, R. A.; Schaefer, W. P.; Serfas, M.; Bercaw, J. E. Organometallics 1987, 6, 1219-1226. (h) McDade, C.; Green, J. C.; Bercaw, J. E. Organometallics 1982, 1, 1629-1634. (44) In general, Cp′2NdCH(TMS)2- and Cp′2SmCH(TMS)2-mediated hydroaminations result in distinct color changes concurrent with catalytic initiation and termination. The original green (Nd) and orange (Sm) solutions of alkyl precatalysts in C6D6 or C7D8 instantaneously turn to the characteristic blue and yellow colors, respectively, of the corresponding amine-amido complexes with initiation of catalytic turnover. Upon consumption of the amine substrates, the resulting reaction solutions return to the original colors.

1048 J. Org. Chem., Vol. 69, No. 4, 2004

(NH2nPr)n in C6D6 in the presence of 20-fold excess n-propylamine (A) after heating at 120 °C for 17.8 h, (B) after heating at 120 °C for 107.5 h, (C) after heating at 120 °C for 168 h, and (D) after heating at 120 °C for 282 h.

The structures of catalytically-active organolanthanides involved in hydroamination19b and hydrophosphination17b have been established on the basis of variable-temperature NMR and single-crystal diffraction studies. A catalytically active amine-amido complex (F and G in eq 7), is generated via rapid protonolysis of Ln-CH(TMS)2 or Ln-N(TMS)2 linkages upon substrate addition. Rapid

exchange between the amido group, bound amine, and free amine are observed by dynamic NMR. The thermal stability of this catalytically-active species was monitored with (CGC)Sm- and Cp′2La- in the presence of noncyclizable n-propylamine. When paramagnetic (CGC)Smis employed with 20-fold molar of excess n-propylamine, the 1H NMR spectrum shows only the tBu resonance of catalytically active species at δ 0.998 ppm with no other signals observable. No detectable diminution of this resonance is observed over a period of 10 days at 120 °C (Figure 8). The catalytically-active species (CGC)Sm(NHnPr)(NH2nPr)n is clearly stable at 120 °C for long reaction time periods. Figure 9A shows the Cp′ 1H signal immediately after substrate 16 addition to Cp′2LaCH(TMS)2. The Cp′ signature of the catalytically active Cp′2La(NHR)(NH2R)n species of 16 is detected at δ 2.051 with no overlap with substrate or the product signals. Monitoring the reaction at 120 °C reveals continuous consumption of substrate and product formation (Figure 9B), but no change in the Cp′ signal until substrate consumption is complete. When turnover is complete, the Cp′ resonance decreases in intensity, disappears, and new Cp′ signals appear (presumably, there is no longer substrate bound to catalyst;

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes

FIGURE 10. Kinetic data for the cyclohydroamination 16 f

FIGURE 9. 500 MHz 1H NMR spectra of cyclohydroamination 16 f 17 mediated by Cp′2La at 120 °C (A) after substrate addition, (B) after the completion of the first cyclization reaction, (C) after the addition of the second aliquot of substrate, and (D) after the completion of the second cyclization reaction.

Figure 9B). However, when an additional aliquot of 16 is added to this reaction mixture,45 the original (Cp′2La(NHR)(NH2R)n) Cp′ resonance at δ 2.051 reappears (Figure 9C). The simplest explanation is that the less sterically hindered primary amine substrate efficiently displaces the encumbered secondary amine piperidine product from the catalyst center (eq 8), and regenerates the catalytically-active lanthanide-amine-amido complex I. The subsequent cyclization reaction was monitored by

1 H NMR, and after completion of the second cyclization reaction, the Cp′ resonance of the catalytically active species I again disappears (Figure 9D). By integration, it is determined that 98 ( 1% of the initial Cp′ signal of the catalytically-active Cp′2La(NHR)(NH2R)n species is regenerated upon the second addition of substrate 16 and 95 ( 1% of the turnover frequency is recovered in the second reaction (Figure 10). It is therefore evident that the catalytically active species for 16, Cp′2La-NHR(NH2R)n, is stable over the course of many hours of reaction.

17 mediated by the Cp′2La- catalyst system. The first trial was carried out with Cp′2LaCH(TMS)2. The second trial was carried out with the addition of the same amount of 16 into the first reaction mixture. The lines represent the leasesquares fit to the data points for the first half-life of the reaction.

repulsionsand to examine the scope, mechanism, and selectivity of the reaction, as well as applicability to natural alkaloid synthesis. The results in Table 1 illustrate that L2LnR complexes 5-9 are efficient precatalysts for high-temperature transformations to 2-alkylsubstituted pyrrolidines, piperidines, 2,5-disubstituted pyrrolidines, and indolizidines, demonstrating potential applications to naturally occurring alkaloids. The cyclizations are sensitive to steric hindrance at both the amine as well as olefinic moiety. Although the Cp′2La- catalyst serves as a generally effective mediator for less sterically demanding substrates such as 10, 12, 14, and 16, significant depressions in rates of conversion are observed for an aminoalkene with a methyl substituent at the C1 position (Table 1, entry 5). Apparently, the C1 methyl substituent and the alkene methyl substituent incur significant repulsive steric interactions with the Cp′ methyl groups in the transition state (L). However, efficient reaction rates are observed in cyclohydroaminations of 18 with catalysts offering greater coordinative unsaturation, such as (CGC)Ln- catalysts 7a, 7b, 7c and 7d (Figure 1). The more open CGC coordination environment plausibly releases catalyst-substrate steric repulsion, and decreases the activation energy to access the rigid, four-centered transition state (M).

Discussion Scope of Intramolecular Hydroamination/Cyclization of Amine-Tethered 1,2-Disubstituted Alkenes. The goal of this research was to address a longstanding problem in catalytic aminoalkene hydroaminationsthat of 1,2-disubstituted alkenes, the sluggishness of which originates from electrostatic and steric (45) In the first trial, 28 mg of 16 and 8 mol % of Cp′2LaCH(TMS)2 were charged into an NMR tube equipped with a Teflon valve. In the second trial, the same amount of 16 was added to the reaction mixture in the N2-filled glovebox. Duplicate reactions were carried out in o-xylene-d10 and C6D6, and the results were identical.

In accord with a rate-limiting ring-closure process (Scheme 1, step ii), Thorpe-Ingold effect34 rate enhancements are observed for the substrates bearing gemdimethyl substituents on the tether. Thus, the 10 f 11 transformation is significantly more rapid than that of 14 f 15 (Cp′2La, Nt ) 8.54 h-1 vs 1.26 h-1; CGCSm, Nt ) 3.59 h-1 vs 0.03 h-1). J. Org. Chem, Vol. 69, No. 4, 2004 1049

Ryu et al. SCHEME 2. Proposed Catalytic Cycle for Organolanthanide-Catalyzed Tandem Bicyclization of Amine-Tethered 1,2-Disubstituted Alkene 20

Tandem cyclization processes are an intriguing feature of homogeneous organolanthanide catalysis.46 Cyclohydroamination of 20 was closely monitored by 1H NMR spectroscopy at 125 °C and constant catalyst concentration. The kinetic data show that the internal olefin reacts first even though the relative reactivity of terminal olefins in hydroamination is generally higher than that of internal olefins.1,21a,26 Most likely, medium-sized ninemembered ring formation 20 f O is kinetically/thermodynamically less favored due to the high degree of ring strain47 and transannular interactions47 in the product than in five-membered ring formation (20 f N) despite the relatively high reactivity of the terminal olefins (eq 9). Before consumption of the internal olefin is complete,

the terminal olefinic resonances begin to decrease in intensity. Thus, we propose that this bicyclization reaction proceeds as depicted in Scheme 2. Rapid protonolysis of the (CGC)Ln-E(SiMe3)2 bond produces detectable 1050 J. Org. Chem., Vol. 69, No. 4, 2004

EH(SiMe3)2 and generates lanthanide-amido complex 24. Subsequent olefin insertion via a four-centered insertive transition state (T2) affords lanthanide-alkyl species 25. This intermediate is quickly protonolyzed by excess substrate 20, regenerating lanthanide-amido complex 24. As the concentration of the pyrrolidine intermediate 26 bearing a pendant terminal olefin increases, protonolysis by this species becomes competitive with protonolysis by primary amine 20. Thus, the increased concentration of intermediate 26 favors the formation of the lanthanidepyrrolidinide intermediate 27, and the second catalytic cycle begins to turn over. Terminal olefin insertion into the Ln-N bond of intermediate 27 via a four-centered transition state then affords the corresponding bicyclic lanthanide alkyl 28. Subsequent protonolysis by substrate 20 and/or pyrolidine intermediate 26 releases the final bicyclized product 21. Reaction Selectivity. Excellent trans diastereoselection in the pyrrolidine-forming transformation 18 f 19 (Table 2) can be understood on the basis of steric and conformational effects in a proposed cyclic, sevenmembered envelope-like transition state for olefin insertion (Scheme 3). Nonbonding interactions arising from congestion in the metal coordination sphere should destabilize the sterically more demanding axial methyl conformation (Scheme 3, Tcis). As noted before, the diastereoselectivities of the 18 f 19 ring closures mediated by (CGC)Ln complexes are surprisingly insensitive to lanthanide ion size (Table 2), with the small ionic radius metals exhibiting improved diastereoselectivi(46) For previous examples of organolanthanide-catalyzed tandem bicyclizations, see refs 22 and 23. (47) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95102.

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes SCHEME 3. Proposed Stereochemical Pathways for Organolanthanide-Catalyzed Intramolecular Hydroamination/Cyclization of Amine-Tethered 1,2-Disubstituted Alkenes To Afford transPyrrolidines

amination of substrate 29 reveal enhanced reactivity with Me2SiCp′′2Ln-, and (CGC)Ln-31 (eq 11). In the case of

ties.48 Most likely, the more congested small radius metal complexes such as (CGC)Lu- and (CGC)Yb- suffer greater ligand-substrate C1 nonbonding interactions than at (CGC)Sm- and conformationally favor the less sterically demanding equatorial orientation (Scheme 3). However, this effect should not be particularly sensitive to Ln3+ size variations considering that CGC ligation is already sterically open. The cis diastereoselectivity in tandem bicyclization of 20 can be explained using these same arguments (Schemes 2 and 3). Metal Ion Size and Ancillary Ligand Effects. The present variation in lanthanide ion size and ancillary ligation allow fine-tuning of the catalyst coordination sphere, leading to improved reactivity and selectivity for a variety of substrates such as aminoalkenes,19 aminoalkynes,20 and aminoallenes.21 Metal ion size effects for amine-tethered 1,2-disubstituted alkenes, are analogous to the trend observed for amine-tethered terminal olefins,19 but reflect a sterically more demanding transition state in the turnover-limiting step (olefin insertion to Ln-N bond; Scheme 1, step ii) than amine-tethered terminal olefins. The present Cp′2Ln- catalytic system exhibits a reactivity change from Nt ) 0 (125 °C) to Nt ) 8.54 (125 °C) for 10 and from Nt ) 0 (125 °C) to Nt ) 11.5 (125 °C) for 16 on increasing the Ln3+ ionic radius from Y3+ to La3+. Smaller sized metals than Y3+ combined with Cp′2 ligation are ineffective in mediating the cyclization of amine-tethered 1,2-disubstituted alkenes. Presumably the coordination environment of Cp′2Y- is insufficiently open for insertion of sterically hindered 1,2disubstituted alkenes. In fact, opening the coordination sphere with CGC ligation leads to an enhanced cyclization rate (Nt ) ∼3 h-1 (125 °C; eq 10). In regard to ancillary ligand effects, the rate of cyclohydroamination increases with more open ligand systems having smaller ring centroid-Ln-ring centroid or ring centroid-Ln-N angles. Trends observed in cyclohydro(48) Similar trends are observed in the cyclization of amine-tethered terminal olefin 22 f 23 mediated by CGCLn (e.g., Nd, 10:1; Sm, 10:1; Yb, 21:1).30

amine-tethered 1,2-disubstituted alkene cyclohydroaminations, opening the coordination sphere around the metal by changing ancillary ligation does not always correlate with improved reactivity, especially for (CGC)Ln- complexes (Table 5). For the sterically demanding substrate 18, CGC ligation offering a more open coordination sphere around the metal exhibits improved reactivity compared to the relatively sterically congested Cp′2Ln- ligation. However, for sterically less hindered substrates such as 10 and 16, Me2SiCp′′2Ln ligation having electron-donating bis-Cp′′ ligation33 exhibits the highest activity. Kinetic Studies of Hydroamination/Cyclization of Amine-Tethered 1,2-Disubstituted Alkenes. The kinetic data obtained in this study reveal zero-order kinetics in substrate concentration over 1-3 half-lives at the elevated temperatures employed (Figure 5). These data support the idea that this organolanthanidecatalyzed cyclohydroamination traverses a similar reaction coordinate to that previously identified for aminoalkenes19b bearing terminal olefins; turnover-limiting olefin insertion into a Ln-N bond via a four-centered transition state (T1, Scheme 1) is efficaciously coupled to rapid protonolysis of the resulting Ln-C bond. Deviations from zero-order cycloamination kinetics are frequently observed in the (CGC)Ln- systems after one half-life compared to the Cp′2Ln- system. With the larger (CGC)Ln- catalyst centers, the coordination of the Lewis basic product17b,19b,49 is likely more probable, leading to a competitive product inhibition. In contrast, more congested ligation should disfavor coordinative inhibition of the Lewis basic product. The enthalpic barrier of the turnover limiting olefin insertion step of amine-tethered 1,2-disubstituted alkenes, derived from a standard Eyring plot, is expectedly higher than for terminal olefin cyclohydroamination (Table 6). The relatively high activation energy barrier (49) For the examples of the competition for vacant Cp′2LnR coordination sites by Lewis bases, see: (a) Mauermann, H.; Marks, T. J. Organometallics 1985, 4, 200-202. (b) Reference 28. (c) Reference 29a. (d) Jeske, G.; Lauke, H.; Mauermann, H.; Schumann, H.; Marks, T. J. J. Am. Chem. Soc. 1985, 107, 8111-8118. (e) Watson, P. L.; Parshall, G. W. Acc. Chem. Res. 1985, 18, 51-55.

J. Org. Chem, Vol. 69, No. 4, 2004 1051

Ryu et al. TABLE 6. Activation Parameter Comparison for Intramolecular Hydroamination/Cyclization Reaction

consistent with entropic trends for organolanthanidemediated cyclohydroamination of aminoalkynes,20 aminoallenes,21 and aminoalkenes bearing terminal olefins,19b which imply highly organized, polar transition states characteristic of many d0, fn-centered transformations. Interestingly, the present ∆Sq value is comparable to that for an amine-tethered terminal olefin, suggesting a minor role for alkene substituents. Moreover, the transition state appears to be more highly organized than the structurally similar disubstituted allene. Conclusions

a Determined using Me SiCp′′ SmCH(TMS) in o-xylene-d . 2 2 2 10 Determined using Cp′2LaCH(TMS)2 in toluene-d8.21a c Determined using Cp′2LaCH(TMS)2 in toluene-d8.19b d Determined using Cp′2SmCH(TMS)2 in toluene-d8.20a

b

in the 1,2-disubstituted olefin insertion step into the Ln-N bond can be reduced by decreasing congestion in the transition state using lanthanide ions of maximum ionic radius and more open ancillary ligation at the elevated temperatures. Modest enthalpic barriers for aminoalkynes, aminoallenes, and aminoalkenes bearing terminal olefin tethers or internal olefin tethers reflect the suggested concerted transition state (T1, Scheme 1) in which significant bond formation energetically compensates for bond-breaking. In the present study, cyclohydroamination of an aminoalkene bearing an internal olefin exhibits the highest ∆Hq value for this series of substrates (Table 6). Most likely the high ∆Hq value originates from the steric and electrostatic repulsions of disubstituted olefin. The large negative ∆Sq value is

1052 J. Org. Chem., Vol. 69, No. 4, 2004

The present results demonstrate that the organolanthanide precatalysts are effective for enantioselective/ diastereoselective intramolecular hydroamination/cyclization of encumbered amine-tethered unactivated 1,2disubstituted alkenes under elevated thermal conditions. The present process provides 2-alkyl-substituted pyrrolidines, piperidines, and disubstituted pyrrolidines in excellent yield, diastereoselectivities, and moderate enantioselectivities. In addition, the sequential tandem bicyclization of amines bearing separated internal and terminal olefins can be readily applied to stereoselective indolizidine synthesis. The catalytically-active species, lanthanide-amido-amine complexes, are thermally robust.

Acknowledgment. Financial support by the NSF (CHE-0078998) is gratefully acknowledged. Supporting Information Available: Complete experimental procedure and spectral data for all synthetic compounds. 1H and 13C NMR spectra of representative compounds. This material is available free of charge via the Internet at http://pubs.acs.org. JO035417C