Organolanthanide-Catalyzed Intramolecular Hydroamination/Cyclization/Bicyclization of Sterically Encumbered Substrates. Scope, Selectivity, and Catalyst Thermal Stability for Amine-Tethered Unactivated 1,2-Disubstituted Alkenes

Article abstract of DOI:10.1021/jo035417c

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(η ⁵-Me₄C₅)(^tBuN)]LnE(TMS)₂ (Ln = Sm, Y, Yb, Lu; E = N, CH) as precatalysts. [Me₂Si(η ⁵-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 C ₁-symmetric organolanthanide catalysts of the type [Me ₂Si(OHF)(CpR*)]LnN(TMS)₂ (OHF = η ⁵-octahydrofluorenyl; Cp = η⁵-C₅H ₃; R* = (-)-menthyl; Ln = Sm, Y), and [Me₂Si(η ⁵-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 NH₂CH₂CMe₂CH₂CH=CH(CH ₂)₂CH=CH₂ is regiospecifically bicyclized by [Me₂Si(η⁵-Me₄C₅)( ^tBuN)]LnE(TMS)₂ to the corresponding indolizidine skeleton in good yield and high diastereoselectivity. Thermolysis of (η ⁵-Me₅C₅)₂LaCH(TMS)₂ in cyclohexane-d₁₂ at 120 °C rapidly releases CH ₂(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 (η ⁵,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(η ⁵-Me₄C₅)(^tBuN)]Sm(NHR)(NH ₂R)_n are shown to be thermally robust species.

Full text of DOI:10.1021/jo035417c

Or ga n ola n th a n id e-Ca ta lyzed In tr a m olecu la r Hyd r oa m in a tion /
Cycliza tion /Bicycliza tion of Ster ica lly En cu m ber ed Su bstr a tes.
Scop e, Selectivity, a n d Ca ta lyst Th er m a l Sta bility for
Am in e-Teth er ed Un a ctiva ted 1,2-Disu bstitu ted Alk en es
J ae-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
t-marks@northwestern.edu
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 bicy-
clized 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 com-
plexes (η5-Me5C5)2La(NHR)(NH2R)n and [Me2Si(η5-Me4C5)(tBuN)]Sm(NHR)(NH2R)n are shown to
be thermally robust species.
In tr od u ction
mediated by a variety of metal ions (eq 1). Nonetheless,
Cyclizations of amine-tethered 1,2-disubstituted al-
kenes 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 unacti-
vated 1,2-disubstituted olefins would be a synthetically
valuable and straightforward approach for the construc-
tion of naturally occurring alkaloid skeletons, it has been
a difficult process to achieve.1 Recently, substantial
literature has emerged concerning the catalytic hy-
droamination of internal olefins activated by neighboring
functional groups2 (e.g., conjugated dienes,3 vinylarenes,4
R,â-unsaturated ketones,5 R,â-unsaturated esters,6 R,â-
unsaturated nitro compounds, and acrylonitrile6,7) and
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.
† 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, 1579-
1594 and references therein.
(5) Bozel, J . J .; Hegedus, L. S. J . Org. Chem. 1981, 46, 2561-2563.
(6) Kawatsura, M.; Hartwig, J . F. Organometallics 2001, 20, 1960-
1964.
(7) Fadini, L.; Togni, A. Chem. Commun. 2003, 30-31.
10.1021/jo035417c CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/21/2004
1038
J . Org. Chem. 2004, 69, 1038-1052

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes
olefins. N-H bond insertion across electron-rich, unac-
tivated 1,2-disubstituted alkenes is impeded by a high
enthalpic barrier, which likely reflects steric encum-
brance 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 repul-
sion. In both cases, catalytic amine addition to unacti-
vated internal olefins is markedly sensitive to the steric
encumbrance of the olefin substituents, leading to slug-
gish reaction rates and/or low yields.
Organolanthanide-catalyzed heteroatom hydroelementa-
tion14-17 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 path-
ways, (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 poten-
tially one of the most efficient and elegant processes for
the construction of naturally occurring alkaloid skeletons.
Over the past decade, catalytic regio-/diastereo-/enanti-
oselective intramolecular cyclohydroamination catalyzed
by trivalent lanthanocene complexes18 has been exten-
sively investigated. Major advances include cyclohy-
droaminations of aminoalkenes,19 aminoalkynes,20 ami-
noallenes,21 tandem bicyclizations of aminodienes, amino-
(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 hydroami-
nation of norbornene: Casalnuovo, A. L.; Calabrese, J . C.; Milstein,
D. J . Am. Chem. Soc. 1988, 110, 6738-6744. (d) Ir-catalyzed asym-
metric 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 Organome-
tallic Compounds; Cornils, B., Herrmann, W. A., Eds.; VCH: Wein-
heim, 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, 104-
114. (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, 3705-
3723. (q) McGrane, P. L.; J ensen, 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, 12670-
12671. (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, 539-
546. (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, 1306-
1319. (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.
(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. Organo-
metallics 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.; J ulius, 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) Molan-
der, 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, 4108-
4109.
(20) (a) Li, Y.; Marks, T. J . J . Am. Chem. Soc. 1996, 118, 9295-
9306. (b) Li, Y.; Fu, P.-F.; Marks, T. J . Organometallics 1994, 13, 439-
440.
(21) (a) Arredondo, V. M.; McDonald, F. E.; Marks, T. J . Organo-
metallics 1999, 18, 1949-1960. (b) Arredondo, V. M.; McDonald, F.
E.; Marks, T. J . J . Am. Chem. Soc. 1998, 120, 4871-4872.
J . Org. Chem, Vol. 69, No. 4, 2004 1039

Ryu et al.
SCHEME 1. P r op osed Ca ta lytic Cycle for
Or ga n ola n th a n id e-Ca ta lyzed Cycloh yd r o-
a m in a tion of Am in oa lk en es
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′ func-
tionalities 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 indi-
cate that Ln-N bond addition to RHCdCHR′ is ham-
pered 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 separa-
tion imbalance in the reasonably well-characterized
transition state19b (T1, Scheme 1), both deriving from the
sterically demanding, electron-donating alkyl substitu-
tion. The steric sensitivity of the olefin insertion step also
doubtless reflects subtle changes in the catalyst coordina-
tion 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 organolanthanide-
catalyzed 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 orga-
nolanthanide precatalysts combined with higher reaction
temperatures to extend aminoalkene cyclohydroamina-
tions to 1,2-disubstituted alkenes. In addition, a full
account of reaction scope, diastereo- and enantioselec-
tivity, metal and ancillary ligand effects, reaction kinet-
ics, and the thermal stability of the precatalysts and
catalytically active species are presented.
diynes, and aminoenynes,22 as well as recent application
to the stereoselective synthesis of the bicyclic alkaloid,
(+)-xenovenine.23 The mechanistically well-defined cata-
lytic cycle19-23 for organolanthanide-catalyzed hydroami-
nation (Scheme 1) demonstrates that after rapid and
quantitative protonolysis of hydrocarbyl or amido pre-
catalysts (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
Resu lts
The principal goal of this study was to address a
significant current limitation of aminoalkene hydroami-
nation and to explore in detail the scope and selectivity
of the organolanthanide-catalyzed intramolecular hy-
droamination/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 turn-
over 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.
(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.; Kana-
bus-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.
Or ga n ola n th a n id e P r eca ta lysts for Hyd r oa m in a -
tion of 1,2-Disu bstitu ted Alk en es a n d Ca ta lyst Gen -
(26) Molander, G. A.; Dowdy, E. D. J . Org. Chem. 1998, 63, 8983-
8988.
(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: Wash-
ington, DC, 2001; Abstract ORGN 265.
1040 J . Org. Chem., Vol. 69, No. 4, 2004

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes
F IGURE 1. Organolanthanide precatalysts for hydroamination of 1,2-disubstituted alkenes.
er a tion . Figure 1 depicts the organolanthanide precat-
alysts 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 in-
ternal 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
1
lead to unassignable peaks in the H NMR.
Routes into the catalytic cycle are well-established for
F IGURE 2. 1H 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.
amino-olefin hydroamination.19b Amine precoordination
to the lanthanide metal leads to essentially instanta-
neous 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 com-
plex, 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 con-
gested precatalysts such as 8b are employed, precatalyst
peaks are observed initially, and Ln-C/Ln-N protonoly-
sis requires several minutes. These differences in proto-
nolysis 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
1
that, by H 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 peri-
ods.
Scop e of In t r a m olecu la r H yd r oa m in a t ion /Cy-
cliza tion of Am in e-Teth er ed 1,2-Disu bstitu ted Al-
k en es. 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-
(28) J eske, G.; Lauke, H.; Mauermann, H.; Swepston, P. N.; Schu-
mann, H.; Marks, T. J . J . Am. Chem. Soc. 1985, 107, 8091-8103.
(29) (a) J eske, 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 . Organo-
metallics 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.
(32) A substrate bearing an R-methyl substituent such as 2-amino-
hept-5-ene (18) exhibits a relatively long induction period.
J . Org. Chem, Vol. 69, No. 4, 2004 1041

Ryu et al.
TABLE 1. Or ga n ola n th a n id e-Ca ta lyzed In tr a m olecu la r Hyd r oa m in a tion /Cycliza tion of Am in es Teth er ed to
Un a ctiva ted 1,2-Disu bstitu ted Alk en esa
a
b
Conditions: All reactions conducted with 5 mol % precatalyst in o-xylene-d10 at 125 °C (unless otherwise indicated). Determined in
o-xylene-d10. c Determined by 1H NMR spectroscopy and GC-MS. Isolated yield in NMR-scale reaction. e Isolated yield of the
d
corresponding HCl salt in preparative-scale reaction; the reactions were conducted in C6H6. f 10 mol % of precatalysts was employed.
g
Turnover frequency (Nt) could not be accurately determined by NMR due to paramagnetism; reactions were quenched after 36 h (10 f
11), 5 d (16 f 17), 48 h (18 f 19), and 2 d (20 f 21). Cis/trans ) 81:19 ratio observed by 1H NMR spectroscopy and GC-MS. Isolation
h
yield of the free amine.
catalysts for clean and in most cases quantitative in-
tramolecular hydroamination/cyclization of amine-teth-
ered 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 120-
125 °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 fre-
quencies 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
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 bind-
ing. Preparative-scale reactions were carried out in sealed
reaction tubes at 120-125 °C. The final pyrrolidine,
piperidine, and indolizidine products were vacuum trans-
ferred with other volatiles and then treated with anhy-
drous HCl in ether. The resulting hydrochloride salts
were purified by recrystallization. The final hydroami-
nation/cyclization products were characterized by 1H, 13C,
2D-NMR spectroscopy, GC/MS, high-resolution MS, and
elemental analysis.
The present high-temperature hydroamination/cycliza-
tion process for amine-tethered 1,2-disubstituted alkenes
is effective in catalytic transformations to form 2-alkyl-
substituted piperidines, pyrrolidines, 2,5-disubstituted
pyrrolidines, and indolizidines. The present study reveals
that thermally stable and reactive bis-cyclopenta-
dienyl precatalysts such as Cp′2LaCH(SiMe3)2 (5a ) and
1042 J . Org. Chem., Vol. 69, No. 4, 2004

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes
TABLE 2. Dia ster eoselectivities in th e In tr a m olecu la r
Hyd r oa m in a tion /Cycliza tion of tr a n s-2-Am in oh ep t-5-en e
(18)
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 “con-
tained geometry” precatalysts having more open coordi-
nation environments and high thermal stability such as
(CGC)LnE(SiMe3)2 (7a -d ) are the most effective pre-
catalysts 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 lanthanide-
centered hydroamination activity over that of CGC-
ligation 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 ami-
noalkenes 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 proto-
nolysis of the Ln-C bond (eq 2). Entry 6 in Table 1 also
entry
precatalysts
Nt trans/ cisa conversion (%)
1
2
3
4
(CGC)SmN(TMS)2 (7a ) 0.41
11:1
16:1
15:1
15:1
95
90
91
77
(CGC)YN(TMS)2 (7b)
0.23
(CGC)YbCH(TMS)2 (7c)
b
(CGC)LuCH(TMS)2 (7d ) 0.23
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 ob-
served at 125°C over a period of 5 days when using
Cp′2LaCH(SiMe3)2.
Rea ction Selectivity. In principle, cyclization of
aminoheptene 18 could afford a mixture of trans- and cis-
2-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 invari-
ant with conversion and do not change after completion
of the reaction (i.e., ring closure is essentially irrevers-
ible). The (CGC)Ln- catalytic system demonstrates
superior diastereoselectivity in the cyclohydroamination
of 22 than the Cp′2Ln-, Me2SiCp′′2Ln-, and Et2-
SiCp′′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-
reveals that direct insertion of the terminal CdC func-
tionality 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
1
reaction, intermediate pyrrolidine A is observable by H
NMR spectroscopy.
(33) For examples where electron-donating metallocene ligands
exhibit higher activities in olefin polymerization, see: (a) Ewen, J . A.;
Elder, M. J .; J ones, 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 ., J r.; Nickias, P. N.; Roof, G. R.; Waele, P. D.; Abboud,
K. A. Organometallics 2001, 20, 2663-2665. (c) Ewen, J . A.; J ones, R.
L.; Elder, M. J .; Rheingold, A. L.; Liable-Sands, L. M. J . Am. Chem.
Soc. 1998, 120, 10786-10787.
(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. En a n tioselectivities in th e In tr a m olecu la r Hyd r oa m in a tion /Cycliza tion of Su bstr a tes 10, 12, a n d 16
Ca ta lyzed by C1-Sym m etr ic Ch ir a l Ca ta lysts 8 a n d 9a
a
b
Conditions: All reactions conducted with 5 mol % precatalyst in C6D6 (unless otherwise indicated). R* ) (-)-menthyl. The reaction
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 spec-
troscopy. Presumably, trans selectivity depends on steric/
conformational effects in the (CGC)Ln-amido transition
state. A possible mechanistic pathway is considered in
the Discussion.
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 epimer-
ization under catalytic hydroamination conditions to
afford mixtures of (R)- and (S)-configurational isomers
(e.g., eq 4). For the (-)-menthyl Me2SiCp′′(CpR*)Ln-
The chiral organolanthanide precatalysts Me2Si(OHF)-
36
37
(CpR*)LnN(TMS)2 and Me2SiCp′′(CpR*)SmN(TMS)2
(Figure 1, catalysts 8 and 9) are partially effective in the
asymmetric cyclohydroamination of amine-tethered 1,2-
disubstituted alkenes (Table 3) at 80-100 °C. It was
found that 2,2-dimethylhex-4-enylamine (10) and 2,2-
dimethyl-hept-4-enylamine (12) undergo sluggish cycliza-
tion 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-dimethylaminohept-
5-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 hydroamina-
tion/cyclizations.17-19 As might be expected, turnover
frequencies observed with the Me2SiCp′′(CpR*)Sm- cata-
lyst (9a ) are significantly greater than those observed
with the Me2Si(OHF)(CpR*)Sm- catalyst (8a ). Presum-
ably 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
complexes, a 95:5 S/R equilibrium epimer ratio is estab-
lished in the presence of a 40-50-fold excess of n-
propylamine 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
(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, 10212-
10240. (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.
(38) For an example of the separation of 2-substituted piperidines,
see: Hyun, M. H.; J in, J . S.; Lee, W. Bull. Korean Chem. Soc. 1997,
18, 336-339.
1044 J . Org. Chem., Vol. 69, No. 4, 2004

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes
F IGURE 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 20-
fold 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, aminoal-
kenes 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 epimeriza-
tion 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 rela-
tively 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,
F IGURE 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 H 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.
1
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).
Meta l a n d Liga n d Effects on th e Ca ta lytic P r o-
cess. In principle, the steric sensitivity of the turnover-
limiting olefin insertion step reflects subtle changes in
the catalyst coordination environment. In fact, organo-
lanthanide-catalyzed cyclohydroamination processes ex-
hibit 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-di-
substituted 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.
(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.
J . Org. Chem, Vol. 69, No. 4, 2004 1045

Ryu et al.
TABLE 4. La n th a n id e Ion Size Effects on th e Tu r n over
F r equ en cies for Cycloh yd r oa m in a tion of Am in es
Teth er ed to Un a ctiva ted 1,2-Disu bstitu ted Alk en es
TABLE 5. An cilla r y Liga tion Effect on th e Tu r n over
F r equ en cy for Cycloh yd r oa m in a tion of Am in es Teth er ed
to Un a ctiva ted 1,2-Disu bstitu ted Alk en es
a
b
Eight-coordinate ionic radii. All rates measured in o-xylene-
a
b
Angle between centroid-Ln-centroid from refs 29-31. All
d10 at 125 °C with 5 mol % of precatalyst.
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 cata-
lytic activity for cyclohydroamination of amine-tethered
1,2-disubstituted alkenes is observed with the coordina-
tively 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′2Ln-
complexes and exhibit enhanced reactivity for cyclohy-
droamintion 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).
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
Kin etic Stu d ies of Hyd r oa m in a tion /Cycliza tion of
Am in e-Teth er ed 1,2-Disu bstitu ted Alk en es. Quan-
titative kinetic studies of the cyclization of 1,2-disubsti-
tuted 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 con-
version (Figure 5A) suggests zero-order dependence on
substrate concentration in analogy to the cyclohydroami-
nation 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 decom-
position is evident (see the discussion on the thermal
stability of catalysts for details).
Variable-temperature kinetic studies were conducted
1
by in situ H NMR on transformation 10 f 11 mediated
by Me2SiCp′′2Sm-. Data are shown in Figure 6A normal-
ized to the CH2(TMS)2 internal standard. The cyclization
rate for 10 f 11 mediated by Me2SiCp′′2Sm- is inde-
pendent of substrate concentration over a 30 °C temper-
1046 J . Org. Chem., Vol. 69, No. 4, 2004

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes
F IGURE 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).
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
F IGURE 5. Ratio of substrate 10: lanthanide complex
concentration as a function of time at 125 °C. (A) Transforma-
tion 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)Sm-
catalyst. The line is least-squares fit to the data points for the
first half-life (linear part).
P r eca ta lyst Th er m a l Sta bility. 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 catalytically-
active 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 precata-
lyst Cp′2LaCH(TMS)2 decomposes rapidly. The diminu-
tion of precatalyst Cp′ resonances at δ 2.015 and 1.972
ppm, and the quantitative evolution of CH2(TMS)2 reso-
1
nances at δ 0.030 and -0.268 ppm are observed by H
NMR. The zero-order kinetic behavior and relatively
rapid decomposition profile of the Cp′2La-hydrocarbyl
precursor suggests an intramolecular thermolytic path-
way, likely involving ring hydrogen C-H activating
metalation by the large ionic radius metal La3+ and η5,η1-
Me4C5CH2- 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 decom-
poses via intramolecular C-H activation and reacts
further to form a thermodynamically stable tetranuclear
F IGURE 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-dimethylami-
nohex-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.
(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.
ature range (95-125 °C), suggesting zero-order behavior
in substrate. Standard Eyring and Arrhenius kinetic
J . Org. Chem, Vol. 69, No. 4, 2004 1047

Ryu et al.
complex E which was characterized by X-ray crystal-
lography.43d A similar decomposition route can be envi-
sioned for Cp′2LaCH(TMS)2.
F IGURE 8. 400 MHz H NMR spectra of (CGC)Sm(NHnPr)-
(NH2nPr)n in C6D6 in the presence of 20-fold excess n-propyl-
amine (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.
1
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 prod-
uct, respectively. Thus, it appears that of any η5,η1-Me4C5-
CH2- species43 readily revert to the active catalyst upon
protonolysis by amine substrates (eq 6). Clearly, precata-
lyst thermolysis does not adversely affect the activity of
the catalytically active species.
The structures of catalytically-active organolanthanides
involved in hydroamination19b and hydrophosphination17b
have been established on the basis of variable-tempera-
ture NMR and single-crystal diffraction studies. A cata-
lytically 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 noncyc-
lizable n-propylamine. When paramagnetic (CGC)Sm-
is employed with 20-fold molar of excess n-propylamine,
1
t
the H NMR spectrum shows only the Bu 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.
(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. Organome-
tallics 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. Organometal-
lics 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.
1
Figure 9A shows the Cp′ H 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 (pre-
sumably, there is no longer substrate bound to catalyst;
1048 J . Org. Chem., Vol. 69, No. 4, 2004

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes
F IGURE 10. Kinetic data for the cyclohydroamination 16 f
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 lease-
squares fit to the data points for the first half-life of the
reaction.
F IGURE 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 cycliza-
tion 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 il-
lustrate that L2LnR complexes 5-9 are efficient precata-
lysts for high-temperature transformations to 2-alkyl-
substituted pyrrolidines, piperidines, 2,5-disubstituted
pyrrolidines, and indolizidines, demonstrating potential
applications to naturally occurring alkaloids. The cycliza-
tions 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 cyclohydroami-
nations 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 environ-
ment plausibly releases catalyst-substrate steric repul-
sion, and decreases the activation energy to access the
rigid, four-centered transition state (M).
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
1H 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.
Discu ssion
Scop e of In t r a m olecu la r H yd r oa m in a t ion /Cy-
cliza tion of Am in e-Teth er ed 1,2-Disu bstitu ted Al-
k en es. The goal of this research was to address a long-
standing problem in catalytic aminoalkene hydro-
aminationsthat of 1,2-disubstituted alkenes, the slug-
gishness of which originates from electrostatic and steric
In accord with a rate-limiting ring-closure process
(Scheme 1, step ii), Thorpe-Ingold effect34 rate enhance-
ments are observed for the substrates bearing gem-
dimethyl 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).
(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.
J . Org. Chem, Vol. 69, No. 4, 2004 1049

Ryu et al.
SCHEME 2. P r op osed Ca ta lytic Cycle for Or ga n ola n th a n id e-Ca ta lyzed Ta n d em Bicycliza tion of
Am in e-Teth er ed 1,2-Disu bstitu ted Alk en e 20
Tandem cyclization processes are an intriguing feature
of homogeneous organolanthanide catalysis.46 Cyclohy-
droamination of 20 was closely monitored by H NMR
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 lanthanide-
pyrrolidinide 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 sub-
strate 20 and/or pyrolidine intermediate 26 releases the
final bicyclized product 21.
1
spectroscopy at 125 °C and constant catalyst concentra-
tion. 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 nine-
membered ring formation 20 f O is kinetically/thermo-
dynamically 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,
Rea ction Selectivity. Excellent trans diastereoselec-
tion 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, seven-
membered envelope-like transition state for olefin inser-
tion (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 medi-
ated by (CGC)Ln complexes are surprisingly insensitive
to lanthanide ion size (Table 2), with the small ionic
radius metals exhibiting improved diastereoselectivi-
the terminal olefinic resonances begin to decrease in
intensity. Thus, we propose that this bicyclization reac-
tion proceeds as depicted in Scheme 2. Rapid protonolysis
of the (CGC)Ln-E(SiMe3)2 bond produces detectable
(46) For previous examples of organolanthanide-catalyzed tandem
bicyclizations, see refs 22 and 23.
(47) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95-
102.
1050 J . Org. Chem., Vol. 69, No. 4, 2004

Amine-Tethered Unactivated 1,2-Disubstituted Alkenes
SCHEME 3. P r op osed Ster eoch em ica l P a th w a ys
for Or ga n ola n th a n id e-Ca ta lyzed In tr a m olecu la r
Hyd r oa m in a tion /Cycliza tion of Am in e-Teth er ed
1,2-Disu bstitu ted Alk en es To Affor d tr a n s-
P yr r olid in es
amination of substrate 29 reveal enhanced reactivity with
Me2SiCp′′2Ln-, and (CGC)Ln-31 (eq 11). In the case of
amine-tethered 1,2-disubstituted alkene cyclohydroami-
nations, 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 coordi-
nation sphere around the metal exhibits improved reac-
tivity 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.
Kin etic Stu d ies of Hyd r oa m in a tion /Cycliza tion of
Am in e-Teth er ed 1,2-Disu bstitu ted Alk en es. The ki-
netic 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 organolanthanide-
catalyzed cyclohydroamination traverses a similar reac-
tion coordinate to that previously identified for amino-
alkenes19b 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. Devia-
tions from zero-order cycloamination kinetics are fre-
quently 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.
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).
Meta l Ion Size a n d An cilla r y Liga n d 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 ami-
noalkynes,20 and aminoallenes.21 Metal ion size effects
for amine-tethered 1,2-disubstituted alkenes, are analo-
gous to the trend observed for amine-tethered terminal
olefins,19 but reflect a sterically more demanding transi-
tion 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 cy-
clization of amine-tethered 1,2-disubstituted alkenes.
Presumably the coordination environment of Cp′2Y- is
insufficiently open for insertion of sterically hindered 1,2-
disubstituted alkenes. In fact, opening the coordination
sphere with CGC ligation leads to an enhanced cycliza-
tion rate (Nt ) ∼3 h-1 (125 °C; eq 10).
The enthalpic barrier of the turnover limiting olefin
insertion step of amine-tethered 1,2-disubstituted alk-
enes, derived from a standard Eyring plot, is expectedly
higher than for terminal olefin cyclohydroamination
(Table 6). The relatively high activation energy barrier
In regard to ancillary ligand effects, the rate of cyclo-
hydroamination increases with more open ligand systems
having smaller ring centroid-Ln-ring centroid or ring
centroid-Ln-N angles. Trends observed in cyclohydro-
(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) J eske, 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.
(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
J . Org. Chem, Vol. 69, No. 4, 2004 1051

Ryu et al.
TABLE 6. Activa tion P a r a m eter Com p a r ison for
In tr a m olecu la r Hyd r oa m in a tion /Cycliza tion Rea ction
consistent with entropic trends for organolanthanide-
mediated cyclohydroamination of aminoalkynes,20 ami-
noallenes,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.
Con clu sion s
The present results demonstrate that the organolan-
thanide precatalysts are effective for enantioselective/
diastereoselective intramolecular hydroamination/cy-
clization of encumbered amine-tethered unactivated 1,2-
disubstituted alkenes under elevated thermal conditions.
The present process provides 2-alkyl-substituted pyrro-
lidines, piperidines, and disubstituted pyrrolidines in
excellent yield, diastereoselectivities, and moderate enan-
tioselectivities. In addition, the sequential tandem bicy-
clization of amines bearing separated internal and ter-
minal olefins can be readily applied to stereoselective
indolizidine synthesis. The catalytically-active species,
lanthanide-amido-amine complexes, are thermally ro-
bust.
a
Determined using Me2SiCp′′2SmCH(TMS)2 in o-xylene-d10
.
Determined using Cp′2LaCH(TMS)2 in toluene-d8.21a c Deter-
b
mined using Cp′2LaCH(TMS)2 in toluene-d8.19b
using Cp′2SmCH(TMS)2 in toluene-d8.20a
Determined
d
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 com-
pensates for bond-breaking. In the present study, cyclo-
hydroamination 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
Ack n ow led gm en t. Financial support by the NSF
(CHE-0078998) is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental procedure and spectral data for all synthetic com-
pounds. 1H and 13C NMR spectra of representative compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O035417C
1052 J . Org. Chem., Vol. 69, No. 4, 2004