Intramolecular Hydroamination/Cyclization of Conjugated Aminodienes Catalyzed by Organolanthanide Complexes. Scope, Diastereo- and Enantioselectivity, and Reaction Mechanism

Published on Web 12/02/2003

Intramolecular Hydroamination/Cyclization of Conjugated

Aminodienes Catalyzed by Organolanthanide Complexes.

Scope, Diastereo- and Enantioselectivity, and Reaction

Mechanism

Sukwon Hong, Amber M. Kawaoka, and Tobin J. Marks*

Contribution from the Department of Chemistry, Northwestern UniVersity,

2145 Sheridan Road, EVanston, Illinois 60208-3113

Received May 21, 2003; E-mail: t-marks@northwestern.edu

Abstract: Organolanthanide complexes of the general type Cp′₂LnCH(TMS)₂(Cp′ ) η⁵-Me₅C₅; Ln ) La,

Sm, Y; TMS ) SiMe₃) and CGCSmN(TMS)₂(CGC ) Me₂Si(η⁵-Me₄C₅)(^tBuN)) serve as effective precatalysts

for the rapid, regioselective, and highly diastereoselective intramolecular hydroamination/cyclization of

primary and secondary amines tethered to conjugated dienes. The rates of aminodiene cyclizations are

significantly more rapid than those of the corresponding aminoalkenes. This dienyl group rate enhancement

as well as substituent group (R) effects on turnover frequencies is consistent with proposed transition state

electronic demands. Kinetic and mechanistic data parallel monosubstituted aminoalkene hydroamination/

cyclization, with turnover-limiting CdC insertion into the LnsN bond to presumably form an Ln-η³allyl

intermediate, followed by rapid protonolysis of the resulting LnsC linkage. The rate law is first-order in

[catalyst] and zero-order in [aminodiene]. However, depending on the particular substrate and catalyst

combination, deviations from zero-order kinetic behavior reflect competitive product inhibition or self-inhibition

by substrate. Lanthanide ionic radius effects and ancillary ligation effects on turnover frequencies suggest

a sterically more demanding LnsN insertion step than in aminoalkene cyclohydroamination, while a

substantially more negative ∆S^‡implies a more highly organized transition state. Good to excellent

diastereoselectivity is obtained in the synthesis of 2,5-trans-disubstituted pyrrolidines (80% de) and 2,6-

cis-disubstituted piperidines (99% de). Formation of 2-(prop-1-enyl)piperidine using the chiral C₁-symmetric

precatalyst (S)-Me₂Si(OHF)(CpR*)SmN(TMS)₂(OHF ) η⁵-octahydrofluorenyl; Cp ) η⁵-C₅H₃; R* )

(-)-menthyl) proceeds with up to 71% ee. The highly stereoselective feature of aminodiene cyclization is

demonstrated by concise syntheses of naturally occurring alkaloids, (()-pinidine and (+)-coniine from simple

diene precursors.

Introduction

side chains can be found in naturally occurring alkaloids, and

one can easily envision that stereoselective 1,2-disubstitituted

Catalytic N-H addition to C-C multiple bonds is a highly

desirable, atom-economical transformation for the synthesis of

organonitrogen molecules.¹There has been a growing effort to

develop efficient and selective catalysts for this challenging

reaction.^2-5Organolanthanides⁶are highly efficient catalysts for

the inter-⁷and intramolecular hydroamination/cyclization of

aminoalkenes,^8,9aminoalkynes,¹⁰and aminoallenes,¹¹reflecting

the facile insertion of C-C unsaturation into lanthanide-ligand

σ bonds (Scheme 1). Attractive features of organolanthanide

catalysts include very high turnover frequencies, versatile

reaction scope in terms of amines (both aliphatic and aromatic),

substitution pattern and ring size,¹²and high stereoselectivity.

Nevertheless, efficient cyclization of amine-tethered 1,2-disub-

stituted alkenes has remained elusive.^8a,8c,11b,13Various R-alkyl

alkene hydroamination could be a very concise, elegant route

to such substituted azacyles (Figure 1).¹⁴The proposed simpli-

fied mechanism for organolanthanide-catalyzed hydroamination

(2) For recent examples of hydroamination catalyzed by late transition metals,

see: (a) Fadini, L.; Togni, A. Chem. Commun. 2003, 30-31. (b) Shimada,

T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12670-12671. (c) Neff,

V.; Mu¨ller, T. E.; Lercher, J. A. Chem. Commun. 2002, 906-907. (d)

Lutete, L. M.; Kadota, I.; Shibuya, A.; Yamamoto, Y. Heterocycles 2002,

58, 347-357. (e) Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002,

124, 1166-1167. (f) Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F.

J. Am. Chem. Soc. 2002, 124, 3669-3679. (g) Lo¨ber, O.; Kawatsura, M.;

Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366-4367. (h) Minami, T.;

Okamoto, H.; Ikeda, S.; Tanaka, R.; Ozawa, F.; Yoshifuji, M. Angew.

Chem., Int. Ed. 2001, 40, 4501-4503. (i) Hartung, C. G.; Tillack, A.;

Trauthwein, H.; Beller, M. J. Org. Chem. 2001, 66, 6339-6343. (j) Mu¨ller,

T. E.; Berger, M.; Grosche, M.; Herdtweck, E.; Schmidtchen, F. P.

Organometallics 2001, 20, 4384-4393. (k) Kawatsura, M.; Hartwig, J. F.

Organometallics 2001, 20, 1960-1964. (l) Kawatsura, M.; Hartwig, J. F.

J. Am. Chem. Soc. 2000, 122, 9546-9547. (m) Senn, H. M.; Blo¨chl, P. E.;

Togni, A. J. Am. Chem. Soc. 2000, 122, 4098-4107. (n) Vasen, D.; Salzer,

A.; Gerhards, F.; Gais, H.-J.; Stu¨rmer, R.; Bieler, N. H.; Togni, A.

Organometallics 2000, 19, 539-546. (o) Mu¨ller, T. E.; Grosche, M.;

Herdtweck, E.; Pleier, A.-K.; Walter, E.; Yan, Y.-K. Organometallics 2000,

19, 170-183. (p) Burling, S.; Field, L. D.; Messerle, B. A. Organometallics

2000, 19, 87-90.

(1) For recent reviews of catalytic hydroamination, see: (a) Pohlki, F.; Doye,

S. Chem. Soc. ReV. 2003, 32, 104-114. (b) Nobis, M.; Driessen-Ho¨lscher,

B. Angew. Chem., Int. Ed. 2001, 40, 3983-3985. (c) Brunet, J, J.;

Neibecker, D. In Catalytic Heterofunctionalization; Togni, A., Gru¨tzmacher,

H. Eds.; Wiley-VCH: Weinheim, 2001; pp 91-141. (d) Mu¨ller, T. E.;

Beller, M. Chem. ReV. 1998, 98, 675-703.

9

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J. AM. CHEM. SOC. 2003, 125, 15878-15892

Aminodienes Catalyzed by Organolanthanide Complexes

A R T I C L E S

Scheme 1. Simplified Catalytic Cycle for the Organolanthanide-Mediated Hydroamination/Cyclization of Aminoalkenes, Aminoalkynes, and

Aminoallenes

strategies. First, new aminoallene substrates¹¹were developed.

In constrast to aminoalkenes, aminoallene cyclization tolerates

further substitution at the terminal position of allenyl groups,

as previously observed with aminoalkynes.^10cThis methodology

was successfully applied to the concise synthesis of the

pyrrolizidine alkaloid, (+)-xenovenine.^11aHowever, the intrinsic

chirality of an allenyl group¹⁵and the rather sluggish rate of a

(3) For recent examples of hydroamination catalyzed by early transition metals,

see: (a) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem.

Commun. 2003, 586-587. (b) Tillack, A.; Castro, I. G.; Hartung, C. G.;

Beller, M. Angew. Chem., Int. Ed. 2002, 41, 2541-2543. (c) Cao, C.; Shi,

Y.; Odom, A. L. Org. Lett. 2002, 4, 2853-2856. (d) Ong, T.-G.; Yap, G.

P. A.; Richeson, D. S. Organometallics 2002, 21, 2839-2841. (e)

Ackermann, L.; Bergman, R. G. Org. Lett. 2002, 4, 1475-1478. (f)

Heutling, A.; Doye, S. J. Org. Chem. 2002, 67, 1961-1964. (g) Straub, B.

F.; Bergman, R. G. Angew. Chem., Int. Ed. 2001, 40, 4632-4635. (h) Cao,

C.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20, 5011-5013.

(i) Johnson, J. S.; Bergman, R. G. J. Am. Chem. Soc. 2001, 123, 2923-

2924. (j) Shi, Y.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001,

20, 3967-3969. (k) Pohlki, F.; Doye, S. Angew. Chem., Int. Ed. 2001, 40,

2305-2308. (l) Haak, E.; Siebeneicher, H.; Doye, S. Org. Lett. 2000, 2,

1935-1937.

Figure 1. Examples of naturally occurring alkaloids containing various

R-side chains.

involves a turnover-limiting, sterically sensitive olefin insertion

step (Scheme 1, step i) via a four-centered transition state,

followed by rapid protonlysis of the resulting Ln-C bond

(Scheme 1, step ii).^8j,10c,11bThe inherent limitation in 1,2-

disubstituted alkene insertion is reasonably attributed to severe

nonbonded steric repulsions^8c,iand a possible charge separation

imbalance in the relatively well-characterized transition state

(A).^8jPreviously, we addressed this issue via two different

(4) For recent examples of hydroamination catalyzed by actinide metals, see:

(a) Wang, J.; Dash, A. K.; Kapon, M.; Berthet, J.-C.; Ephritikhine, M.;

Eisen, M. S. Chem.sEur. J. 2002, 8, 5384-5396. (b) Straub, T.; Haskel,

A.; Neyroud, T. G.; Kapon, M.; Botoshansky, M.; Eisen, M. S. Organo-

metallics 2001, 20, 5017-5035. (c) Haskel, A.; Straub, T.; Eisen, M. S.

Organometallics 1996, 15, 3773-3775.

(5) For recent examples of base-catalyzed hydroaminations, see: (a) Trost, B.

M.; Tang, W. J. Am. Chem. Soc. 2002, 124, 14542-14543. (b) Hartung,

C. G.; Breindl, C.; Tillack, A.; Beller, M. Tetrahedron 2000, 56, 5157-

5162. For recent examples of acid-catalyzed hydroaminations, see: (c)

Miura, K.; Hosomi, A. Synlett 2003, 143-155. (d) Schlummer, B.; Hartwig,

J. F. Org. Lett. 2002, 4, 1471-1474.

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J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003 15879

A R T I C L E S

Hong et al.

Scheme 2. Proposed Catalytic Cycle for the

Organolanthanide-Mediated Hydroamination of Conjugated

Aminodienes

six-membered ring formation render aminoallenes less attractive

for enantioselective hydroamination/cyclization studies. Second,

we also demonstrated that hydroamination/cyclization of amine-

tethered 1,2-disubstituted alkenes proceeds at elevated reaction

temperatures (120-130 °C) with catalysts of large metal ionic

radii/high coordinative unsaturation.^8a,cHowever, alkyl substitu-

tion on the tether region appears to be necessary for reasonable

turnover frequencies.

Alternatively, from preliminary intermolecular organolan-

thanide-mediated diene hydroamination results,^7bwe envisioned

conjugated diene substrates as attractive precursors for the

synthesis of azacyclic targets. At comparable concentrations,

intermolecular diene hydroamination is significantly more rapid

than alkene hydroamination (eq 1 versus eq 2), and lanthanide

η³-crotyl intermediate B was proposed based upon literature

precedent.¹⁶In addition, note that one of the recent advances

Thermodynamic considerations¹⁷for the prospective orga-

nolanthanide-mediated hydroamination of conjugated dienes

predict that insertion (Scheme 2, step i) is significantly more

exothermic (∼ -19 kcal/mol) than for terminal alkenes (∼0

kcal/mol), whereas the subsequent protonolysis (Scheme 2, step

ii) is slightly endothermic (∼ +4 or +7 kcal/mol), unlike the

exothermic protonolysis for the terminal alkene cycle (∼ -13

kcal/mol).¹⁸In our previous communication, we reported that

this transformation proceeds smoothly for a range of substrates

with good rates and high diastereo- and enantioselectivity.¹⁹

Attractive features of aminodiene cyclizations are seen to include

significant rate enhancements versus terminal alkene substrates

and high stereoselectivities as demonstrated in the concise

syntheses of the natural products, (()-pinidine and (+)-coniine.

Herein we present comprehensive kinetic/mechanistic studies

on aminodiene hydroamination and discuss further optimizing

efforts on diastereo- and enantioselectivity. In this full account,

reaction scope, various factors affecting reaction rates and

stereoselectivity, and kinetic observations are discussed/

in late transition metal-mediated hydroamination systems have

been made by utilizing conjugated alkenes such as styrenes^2e,l

and 1,3-dienes^2f,gfor Pd-catalyzed intermolecular hydroamina-

tion.

(6) For recent organolanthanide reviews, see: (a) Aspinall, H. C. Chem. ReV.

2002, 1807-1850. (b) Edelmann, F. T.; Freckmann, D. M. M.; Schumann,

H. Chem. ReV. 2002, 1851-1896. (c) Arndt, S.; Okuda, J. Chem. ReV.

2002, 1953-1976. (d) Molander, G. A.; Romero, J. A. C. Chem. ReV. 2002,

2161-2185. (e) Topics in Organometallic Chemistry; Kobayashi, S. Ed.;

Springer: Berlin, 1999; Vol 2. (f) Edelmann, F. T. Top. Curr. Chem. 1996,

179, 247-276. (g) Schumann, H.; Meese-Marktscheffel, J. A.; Esser, L.

Chem. ReV. 1995, 95, 865-986. (h) Schaverien, C. J. AdV. Organomet.

Chem. 1994, 36, 283-362.

(7) (a) Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am Chem. Soc. 2003, 125, 12584-

12605. (b) Li, Y.; Marks, T. J. Organometallics 1996, 15, 3770-3772.

(8) (a) Ryu, J.-S.; McDonald, F. E.; Marks, T. J. J. Org. Chem., in press. (b)

Kim, Y. K.; Livinghouse, T. Angew. Chem., Int. Ed. 2002, 41, 3645-

3647. (c) Ryu, J.-S.; Marks, T. J.; McDonald, F. E. Org. Lett. 2001, 3,

3091-3094. (d) Molander, G. A.; Dowdy, E. D.; Pack, S. K. J. Org. Chem.

2001, 66, 4344-4347. (e) Kim, Y. K.; Livinghouse, T.; Bercaw, J. E.

Tetrahedron Lett. 2001, 42, 2933-2935. (f) Molander, G. A.; Dowdy, E.

D. J. Org. Chem. 1999, 64, 6515-6517. (g) Tian, S.; Arredondo, V. M.;

Stern, C. L.; Marks, T. J. Organometallics 1999, 18, 2568-2570. (h)

Gilbert, A. T.; Davis, B. L.; Emge, T. J.; Broene, R. D. Organometallics

1999, 18, 2125-2132. (i) Molander, G. A.; Dowdy, E. D. J. Org. Chem.

1998, 63, 8983-8988. (j) Gagne´, M. R.; Stern, C. L.; Marks, T. J. J. Am

Chem. Soc. 1992, 114, 275-294. (k) Gagne´, M. R.; Nolan, S. P.; Marks,

T. J. Organometallics 1990, 9, 1716-1718. (l) Gagne´, M. R.; Marks, T. J.

J. Am. Chem. Soc. 1989, 111, 4108-4109.

(9) (a) Douglass, M. R.; Ogasawara, M.; Hong, S.; Metz, M. V.; Marks, T. J.

Organometallics 2002, 21, 283-292. (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.

(10) (a) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757-1771. (b)

Bu¨rgstein, M. R.; Berberich, H.; Roesky, P. W. Organometallics 1998,

17, 1452-1454. (c) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118,

9295-9306. (d) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 707-

708. (e) Li, Y.; Fu, P.-F.; Marks, T. J. Organometallics 1994, 13, 439-

440.

(11) (a) Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem.

Soc. 1999, 121, 3633-3639. (b) Arredondo, V. M.; McDonald, F. E.;

Marks, T. J. Organometallics 1999, 18, 1949-1960. (c) Arredondo, V.

M.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 4871-

4872.

(12) For a discussion of functional group tolerance in organolanthanide catalysis,

see: (a) Molander, G. A. Chemtracts: Org. Chem. 1998, 11, 237-263.

(b) Reference 7a.

(13) Hydroamination of 1,1-disubstituted alkenes has been reported by Molander;⁸ⁱ

however, hydroamination of 1,2-disubstituted alkenes with the same catalyst

was not successful.

(14) For example, the scope of enantioselective intramolecular hydroamination/

cyclization by chiral organolanthanide was previously limited to mono-

substituted alkenes, affording only methyl substituted chiral azacycles.

(15) AgBF₄-mediated cyclization of a chiral aminoallene to afford a 2-substituted

piperidine in 78% ee: Lathbury, D.; Gallagher, T. J. Chem. Soc., Chem.

Commun. 1986, 114-115.

(16) For discussions of η³-lanthanide allyls, see: (a) Evans, W. J.; Ulibarri, T.

A.; Ziller, J. W. J. Am. Chem. Soc. 1990, 112, 2314-2324. (b) Bunel, E.;

Burger, B. J.; Bercaw, J. E. J. Am. Chem. Soc. 1988, 110, 976-978 (c)

Jeske, G.; Lauke, H.; Mauermann, H.; Swepston, P. N.; Schumann, H.;

Marks, T. J. J. Am. Chem. Soc. 1985, 107, 8091-8103.

(17) Bond enthalpy data: (a) Nolan, S. P.; Stern, D.; Marks, T. J. J. Am. Chem.

Soc. 1989, 111, 7844-7853. (b) McMillen, D. F.; Golden, D. M. Annu.

ReV. Phys. Chem. 1982, 33, 493-532.

(18) (a) The ∆H for CH₃NH₂addition to 1,3-butadiene (to yield (CH₂dCHCH₂-

CH₂NH₂)) is estimated to be -12 kcal/mol ((0.6). (b) Pedley, J. B.; Naylor,

R. D.; Kirby, S. P. Thermochemical Data for Organic Compounds, 2nd

ed.; Chapman and Hall: London, 1986. (c) Nolan, S. P.; Stern, D.; Marks,

T. J. J. Am. Chem. Soc. 1989, 111, 7844-7853.

(19) (a) Hong, S.; Marks, T. J. J. Am. Chem. Soc. 2002, 124, 7886-7887. (b)

Hong, S.; Marks, T. J. Abstract of Papers; communicated in part at the

221st National ACS Meeting, San Diego, CA; April 2001; American

Chemical Society: Washington, DC, 2001; abstract INOR 613.

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15880 J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003

Aminodienes Catalyzed by Organolanthanide Complexes

A R T I C L E S

was monitored by ¹H NMR. After the reaction was complete, the

reaction mixture was freeze-thaw degassed and the volatiles were

vacuum transferred into a separate NMR tube. The solvent was removed

on a rotary evaporator at 0 °C to give the product. Alternatively, for

nonvolatile products, filtration of the reaction mixture through a short

pad of silica gel removes the catalyst. The silica gel was rinsed with

Et₂O (5 mL); the fractions were combined and evaporated under reduced

pressure to afford the product.

interpreted in detail and compared/contrasted with previously

identified hydroamination patterns.

Experimental Section

Materials and Methods. All manipulations of air-sensitive materials

were carried out with rigorous exclusion of oxygen and moisture in

flame- or oven-dried Schlenk-type glassware on a dual-manifold

Schlenk line, or interfaced to a high-vacuum line (10^-6Torr), or in a

nitrogen-filled Vacuum Atmospheres glovebox with a high capacity

recirculator (<1 ppm of O₂). Argon (Matheson, prepurified) was

purified by passage through a MnO oxygen-removal column and a

Davison 4A molecular sieve column. Pentane and toluene were dried

using activated alumina columns according to the method described

by Grubbs²⁰and were additionally vacuum-transferred from Na/K alloy

immediately before use if employed for catalyst synthesis or catalytic

reactions. Ether, THF, and dichloromethane were distilled before use

from appropriate drying agents (sodium benzophenone ketyl, Na/K

alloy, CaH₂, respectively) under nitrogen. Chloroform-d was purchased

from Cambridge Isototope Laboratories. Benzene-d₆, toluene-d₈, and

cyclohexane-d₁₂(Cambridge Laboratories; all 99+ atom % D) used

for NMR reactions and kinetic measurements were stored in vacuo over

Na/K alloy in resealable bulbs and were vacuum transferred im-

mediately prior to use. All organic starting materials were purchased

from Aldrich Chemical Co. or Lancaster Synthesis Inc. and were used

without further purification unless otherwise stated. All substrates were

dried twice as solutions in benzene-d₆or toluene-d₈over freshly

activated Davison 4A molecular sieves and were degassed by freeze-

pump-thaw methods. The substrates were then stored in vacuum-tight

storage flasks. The organolanthanide precatalysts Cp′₂LnCH(TMS)₂(Ln

) La, Sm, Y; Cp′) η⁵-Me₅C₅)^16cand CGCLnN(TMS)₂(CGC ) Me₂-

Si(Me₄C₅)(^tBuN); Ln ) Sm, Y)^8gwere prepared according to published

procedures. We thank Dr. Masamichi Ogasawara for a sample of (S)-

Me₂Si(OHF)(CpR*)SmN(TMS)₂(OHF ) η⁵-octahydrofluorenyl; Cp

) η⁵-C₅H₃; R* ) (-)-menthyl).^9a

Low-Temperature NMR-Scale Catalytic Reaction (Table 4, entry

8). In the glovebox, (S)-Me₂Si(OHF)(Cp-(-)-menthyl)SmN(TMS)₂

(14.6 mg, 19.6 µmol) was weighed into a 5-mm NMR tube equipped

with a Teflon valve (J-Young). The tube was then removed from the

glovebox and attached to the high vacuum line. On the vacuum line,

cyclohexane-d₁₂(0.5 mL) was vacuum-transferred and the tube was

evacuated while the cyclohexane solution was frozen at -78° C.

Substrate 5 (0.05 mL of a 1.9 M solution in C₆D₆, 5-fold molar excess)

was added via syringe under an Ar flush. The tube was next evacuated

and backfilled with Ar 3 times while frozen at -78 °C. The tube was

then sealed and thawed while shaking briefly (2 min) to afford a

homogeneous light-yellow solution. The NMR tube was then immersed

in an ice/water bath and kept at 0 °C for 45 days until the color of the

solution changed from light yellow to orange. Although the melting

point of pure C₆D₁₂is +4.75 °C, the reaction mixture was never

observed to be frozen, presumably because of freezing point depression.

After the reaction was complete, the reaction mixture was diluted with

Et₂O (1.5 mL), filtered through a short pad of silica gel, rinsed with

Et₂O (5 mL), and concentrated on a rotary evaporator at 0 °C to give

crude product 6a/b (95:5 by GC-MS) as a pale-yellow oil.

Preparative-Scale Catalytic Reactions (Method 1; in Situ Protec-

tion of Product, Table 1, entry 10). In the glovebox, (S)-Me₂Si(OHF)-

(Cp-(-)-menthyl)SmN(TMS)₂(34.1 mg, 45.8 µmol) was loaded into

a 15-mL storage tube equipped with a magnetic stir bar and J. Young

valve and dissolved in C₆D₆(3 mL). The initial color of the catalyst

solution was orange. Next, 0.50 mL of a solution of 5 in C₆D₆(1.73

M, 0.87 mmol) was added to the catalyst solution via syringe. The

color of the solution changed to light yellow upon the addition of 5.

The tube was then sealed and removed from the glovebox. The solution

was stirred at room temperature for 8 days until the color turned back

to orange. The reaction mixture was next cooled to 0 °C, diluted with

Et₂O (2 mL), and quenched with 2 N NaOH (1.5 mL). Then, benzyl

chloroformate (Cbz-Cl) (0.21 mL, 1.5 mmol) was added dropwise, and

the mixture was allowed to warm to room temperature and stirred

vigorously for 1 h. Next, the aqueous layer was separated and extracted

with Et₂O (3 × 5 mL). The combined organic layers were washed with

brine (5 mL), dried over MgSO₄, filtered, and concentrated to afford

the crude Cbz-protected amine as a pale yellow oil. The crude product

was purified by flash column chromatography (silica gel, hexanes/Et₂O

) 6:1) to afford 203.7 mg (0.79 mmol, 91% yield) of Cbz-6a/b (97:3

E/Z mixture) as a colorless, clear oil.

Physical and Analytical Measurements. NMR spectra were

1

recorded on either a Varian Gemini 300 (FT, 300 MHz, H; 75 MHz,

1

¹³C), Unity- or Mercury-400 (FT, 400 MHz, H; 100 MHz, ¹³C), or

1

Inova-500 (FT, 500 MHz, H; 125 MHz, ¹³C) instrument. Chemical

1

shifts (δ) for H and ¹³C are referenced to internal solvent resonances

and reported relative to SiMe₄. NMR experiments on air-sensitive

samples were conducted in Teflon valve-sealed tubes (J. Young). HRMS

studies were conducted on a VG 70-250 SE instrument with 70 eV

electron impact ionization or chemical ionization using CH₄as a reagent

gas. Elemental analyses were performed by Midwest Microlabs,

Indianapolis, IN. GC-MS analyses were performed using an HP6890

instrument equipped with an HP 5972 detector, an HP-5MS (5% Phenyl

Methyl Siloxane, 30 m × 250 µm × 0.25 µm) capillary column, and

Chemstation software. HPLC analyses were performed using a Waters

Breeze system consisting of a model 1525 binary pump, model 77251

manual injector, and model 2487 dual λ UV/vis detector. Optical

rotations were measured using an Optical Activity AA-100 polarimeter.

IR spectra were recorded using a Biorad FT S60 FTIR instrument.

Typical NMR-Scale Catalytic Reactions. In the glovebox, the

organolanthanide precatalyst (3-8 mg) was weighed into a 5-mm NMR

tube equipped with a Teflon valve (J-Young), and C₆D₆(0.5 mL) was

added. The tube was then removed from the glovebox and attached to

the high vacuum line. On the vacuum line, the tube was evacuated

while the benzene solution was frozen at -78 ° C. The substrate (ca.

1 M in C₆D₆, 0.15-0.3 mL, 10-40-fold molar excess) was added via

syringe under an Ar flush. The tube was next evacuated and backfilled

with Ar 3 times while frozen at -78 °C. The tube was then sealed,

thawed, and brought to the desired temperature, and the ensuing reaction

Preparative-Scale Catalytic Reactions (Method 2, Table 1, entry

8). In the glovebox, CGCSmN(TMS)₂(15.3 mg, 27.3 µmol) was loaded

into a 15-mL storage tube equipped with a magnetic stir bar and J.

Young valve and dissolved in C₆D₆(3 mL). Next, 3 (89.5 mg) was

weighed into a vial and dissolved in C₆D₆(0.6 mL). The resulting

solution was transferred to the catalyst solution using a pipet and rinsed

with C₆D₆(0.4 mL). The tube was then sealed and removed from the

glovebox. The solution was then heated in an oil bath at 60 °C for 18

h. The reaction was then allowed to cool to room temperature, the

solvent was removed on a rotary evaporator, and the crude yellow liquid

was purified by flash column chromatography (silica gel, hexanes/

EtOAc ) 8:1) to afford 63.5 mg (71% yield) of 4a/b as a slightly

yellow liquid.

2-[(E)-Prop-1-enyl]pyrrolidine (2a).^{11b 1}H NMR (400 MHz, C₆D₆)

δ 5.53 (d of quartet, 15.6 Hz, 5.6 Hz, 1H), 5.46 (dd, 15.6 Hz, 6.8 Hz),

3.36 (dt, 7.2 Hz, 6.8 Hz, 1H), 2.90-2.84 (m, 1H), 2.69-2.62 (m, 1H),

1.75-1.67 (m, 1H), 1.58 (d, 5.6 Hz, 3H), 1.61-1.42 (m, 2H), 1.35-

(20) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers,

F. J. Organometallics 1996, 15, 1518-1520.

9

J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003 15881

A R T I C L E S

Hong et al.

1.26 (m, 1H), 1.04 (br s, 1H); ¹³C NMR (125.7 MHz, C₆D₆) δ 135.9,

124.7, 61.5, 47.1, 33.2, 26.0, 18.2. MS (rel abundance): M⁺111.1

(14), 110.1 (22), 96.1 (73), 83.1 (11), 82.1 (13), 70.1 (38), 68.1 (100),

67.1 (12), 41.1 (25), 39.1 (18). HRMS-EI (m/z): [M⁺] calcd for C₇H₁₃N,

111.1048; found, 111.1047.

2-[(Z)-Prop-1-enyl]pyrrolidine (2b).^{11b 13}C NMR (125.7 MHz,

C₆D₆) δ 135.7, 124.5, 56.0, 47.3, 33.4, 26.3, 13.7. MS (rel abun-

dance): M⁺111.1 (14), 110.1 (22), 96.1 (73), 83.1 (11), 82.1 (13),

70.1 (38), 68.1 (100), 67.1 (12), 41.1 (25), 39.1 (18).

Hz, 3H), 1.78-1.49 (m, 5H), 1.48-1.34 (m, 1H); ¹³C NMR (125.7

MHz, CDCl₃) δ 155.9, 137.3, 129.2, 128.6, 128.0, 127.9, 127.1, 67.1,

52.4, 40.2, 29.6, 25.8, 19.6, 18.1. IR (neat) 3063, 3030, 2937, 2857,

1703, 1497, 1445, 1421, 1351, 1355, 1323, 1257. MS (rel abundance):

M⁺259.2 (1), 168.1 (37), 124.1 (20), 92.1 (8), 91.1 (100), 82.1 (9),

65.1 (15), 55.1 (10). HRMS-EI (m/z): [M⁺] calcd for C₁₆H₂₁NO₂,

259.1572; found, 259.1572. Anal. Calcd for C₁₆H₂₁NO₂: C, 74.10; H,

8.16; N, 5.40. Found: C, 73.88; H, 8.23; N, 5.34.

1

3,3-Dimethyl-6-[(E)-prop-1-enyl]piperidine (8a). H NMR (500

2-(Prop-2-enyl)pyrrolidine (2c). ¹³C NMR (125.7 MHz, C₆D₆) δ

137.5, 116.3, 59.0, 41.7, 31.8, 26.2, 26.0. MS (rel abundance): [M -

41]⁺70.1 (100), 68.1 (11), 43.1 (10), 41.1 (12).

MHz, CDCl₃) δ 5.57 (dq, 15.5 Hz, 6 Hz, 1H), 5.46 (dd, 15.5 Hz, 6 Hz,

1H), 2.92-2.89 (m, 1H), 2.59 (dd, 12 Hz, 2 Hz, 1H), 2.46 (d, 12 Hz,

1H), 1.65 (d, 6 Hz, 3H), 1.48-1.22 (m, 4H), 0.97 (s, 3H), 0.83 (s,

3H); ¹³C NMR (125.7 MHz, CDCl₃) δ 135.0, 124.9, 59.0, 58.7, 37.9,

29.8, 29.4, 23.9, 18.1. MS (rel abundance): M⁺153 (31), 138 (97),

125 (25), 110 (58), 96 (30), 82 (51), 70 (77), 68 (100), 67 (38), 55

(29), 41 (51). HRMS-EI (m/z): [M⁺] calcd for C₁₀H₁₉N, 153.1518;

found, 153.1523.

N-Boc-2-[(E)-but-1-enyl]pyrrolidine (Boc-10a). ¹H NMR (400

MHz, CDCl₃): δ 5.49 (br s, 1H), 5.32 (br s, 1H), 4.32 and 4.17 (br s,

1H), 3.38 (br s, 2H), 2.07-1.92 (m, 1H), 2.03 (quintet, 7 Hz, 2H),

1.90-1.73 (m, 2H), 1.70-1.64 (m, 1H), 1.44 (s, 9H), 0.98 (t, 7 Hz,

3H); ¹³C NMR (125.7 MHz, CDCl₃): δ 155.4, 132.2, 129.8, 79.1, 58.9,

46.4, 32.8, 28.7, 25.4, 23.2, 14.0. MS (rel abundance): M⁺225.2 (1),

169.1 (17), 152.1 (17), 140.1 (100), 114.1 (57), 108.1 (9), 96.1 (30),

70.1 (14), 68.1 (11), 67.1 (14), 57.1 (78), 55.1 (11), 43.0 (9), 41.0

(45), 39.0 (16). HRMS-EI (m/z): [M⁺] calcd for C₁₃H₂₃NO₂, 225.1729;

found, 225.1727.

N-Boc-2-[prop-1-enyl]pyrrolidine (Boc-2a/b).^{21 1}H NMR (500

MHz, CDCl₃) δ 5.48 (br s, 1H), 5.35 (br s, 1H), 4.53 (br s, 0.4H), 4.29

and 4.17 (br s, 0.6H), 3.38 (br s, 2H), 2.10-1.75 (m, 3H), 1.70 (d, 6.0

Hz, 3H), 1.64-1.58 (m, 1H), 1.44 (s, 9H). Both isomers exhibit

indistinguishable mass spectra; MS (rel abundance): M⁺211.2 (1),

155.1 (56), 140.1 (100), 138.1 (20), 114.1 (15), 110.1 (13), 96.1 (38),

83.1 (10), 70.1 (15), 68.1 (22), 67.1 (15), 57.1 (100), 56.1 (10), 55.1

(14), 43.0 (13), 42.0 (11), 41.1 (66), 39.0 (28). HRMS-EI (m/z): [M⁺]

calcd for C₁₂H₂₁NO₂, 211.1572; found, 211.1571.

N-Boc-2-(prop-2-enyl)pyrrolidine (Boc-2c).^{21 1}H NMR (500 MHz,

CDCl₃) δ 5.75 (m, 1H), 5.06 (d, 16.5 Hz, 1 H), 5.03 (d, 8.5 Hz, 1H),

3.87 and 3.77 (br s, 1H), 3.40 and 3.32 (br s, 2H), 2.55 and 2.43 (br s,

1H), 2.14 and 2.11 (t, 8.0 Hz, 1H), 1.94-1.69 (m, 4H), 1.47 (s, 9H).

MS (rel abundance): [M - 41]⁺170.1 (9), 114.1 (65), 70.1 (100),

57.1 (84), 41.1 (40), 39.1 (13).

N-Bn-2-[(E)-prop-1-enyl]pyrrolidine (4a). (Isolated by the prepara-

tive-scale method 2) H NMR (400 MHz, CDCl₃): δ 7.38-7.23 (m,

N-Boc-2-(but-2-enyl)pyrrolidine (Boc-10c/d). E/Z ) 76:24 mixture.

¹H NMR (400 MHz, CDCl₃) δ 5.56-5.31 (m, 2H), 3.79-3.71 (m,

1H), 3.40-3.20 (m, 2H), 2.45 (br s, 0.5H), 2.32 (br s, 0.5H), 2.05-

1.98 (m, 1H), 1.85-1.74 (m, 3H), 1.72-1.62 (m, 1H), 1.65 (d, 6.0

Hz, 3H), 1.46 (s, 9H); ¹³C NMR (125.7 MHz, CDCl₃) δ 155.3, 127.9,

127.6, 126.8, 126.2, 79.1, 57.3, 46.9, 46.5, 37.9, 37.1, 30.3, 29.3, 28.8,

23.8, 23.1, 18.3, 13.0. Both isomers exhibit indistingishable mass

spectra; MS (rel abundance): [M - 55]⁺170.1 (17), 152.1 (11), 114.1

(88), 70.1 (100), 57.1 (83), 55.1 (12), 41.1 (37), 39.0 (13).

2-[3-Phenyl-(E)-prop-2-enyl]pyrrolidine (12c). ¹H NMR (400

MHz, CDCl₃) δ 7.36 (d, 8.0 Hz, 2H), 7.30 (t, 7.4 Hz, 2H), 7.21 (t, 7.0

Hz, 1H), 6.46 (d, 16.0 Hz, 1H), 6.24 (dt, 16.0 Hz, 7.2 Hz, 1H), 3.14

(quintet, 6.8 Hz, 1H), 3.06-2.98 (m, 1H), 2.88-2.82 (m, 1H), 2.37 (t,

6.6 Hz, 2H), 1.95-1.86 (m, 1H), 1.84-1.66 (m, 3H), 1.43-1.34 (m,

1H); ¹³C NMR (100.6 MHz, CDCl₃) δ 137.6, 131.7, 128.5, 128.1, 127.1,

126.1, 59.0, 46.7, 40.1, 31.5, 25.6. MS (rel abundance): [M - 70]⁺

117.1 (5), 115.1 (9), 91.1 (5), 71.1 (5), 70.1 (100), 43.1 (5). HRMS-CI

(m/z): [MH⁺] calcd for C₁₃H₁₈N, 188.1439; found, 188.1437.

trans-2-Methyl-5-[(E)-prop-1-enyl]pyrrolidine (trans-14a). ¹H NMR

(500 MHz, C₆D₆) δ 5.50 (d of quartet, 15.3 Hz, 5.5 Hz, 1H), 5.44 (dd,

15.3 Hz, 6.5 Hz, 1H), 3.64 (quartet, 6.5 Hz, 1H), 3.19 (sextet, 6.5 Hz,

1H), 1.89-1.82 (m, 1H), 1.80-1.74 (m, 1H), 1.58 (d, 5.5 Hz, 3H),

1.39 (d of quartet, 12.0 Hz, 8.5 Hz, 1H), 1.12 (d of quartet, 12.0 Hz,

8.5 Hz, 1H), 1.05 (m, 1 H), 1.00 (d, 6.5 Hz, 3H); ¹³C NMR (125.7

MHz, C₆D₆) δ 136.6, 124.0, 60.4, 53.6, 34.9, 34.0, 23.0, 18.2. MS (rel

abundance): M⁺125.1 (11), 124.1 (8), 110.1 (52), 93.1 (8), 84.1 (15),

82.1 (100), 68.0 (18), 67.1 (15), 55.1 (8), 53.0 (8), 44.0 (8), 42.0 (16),

41.0 (26), 39.0 (25). HRMS-EI (m/z): [M⁺] calcd for C₈H₁₅N, 125.1205;

found, 125.1191.

1

5H), 5.66 (d of quartet, 15.0 Hz, 6.4 Hz, 1H), 5.44 (ddd, 15.0 Hz, 8.2

Hz, 1.2 Hz, 1H), 4.07 (d, 12.8 Hz, 1H), 3.05 (d, 12.8 Hz, 1H), 2.95

(dt, 2.0 Hz, 8.2 Hz, 1H), 2.75 (quartet, 8.0 Hz, 1H), 2.09 (quartet, 8.8

Hz, 1H), 2.01-1.88 (m, 1H), 1.83-1.52 (m, 3H), 1.75 (d, 6.4 Hz, 3H);

¹³C NMR (100.6 MHz, CDCl₃) δ 139.7, 133.8, 129.1, 128.2, 127.8,

126.7, 68.0, 58.4, 53.5, 31.9, 22.2, 18.2. MS (rel abundance): M⁺201.2

(17), 200.2 (13), 186.1 (20), 172.1 (12), 160.1 (29), 158.1 (13), 91.1

(100), 82.1 (16), 65.1 (22), 41.1 (16), 39.0 (15). HRMS-EI (m/z): [M⁺]

calcd for C₁₄H₁₉N, 201.1518; found, 201.1511.

2-[(E)-Prop-1-enyl]piperidine (6a).^{11b 1}H NMR (500 MHz, C₆D₆)

δ 5.56-5.48 (m, 2H), 2.92-2.87 (m, 2H), 2.46 (dt, 11.5 Hz, 7.5 Hz,

1H), 1.68-1.64 (m, 1H), 1.60-1.54 (m, 1H), 1.57 (d, 4.5 Hz, 3H),

1.42-1.36 (m, 2H), 1.32-1.18 (m, 2H), 1.00 (s, 1H); ¹³C NMR (125.7

MHz, C₆D₆): δ 136.9, 124.4, 60.0, 47.7, 34.0, 26.9, 25.7, 18.3. MS

(rel abundance): M⁺125.1 (16), 124.1 (13), 110.1 (55), 97.1 (27),

96.1 (29), 84.1 (37), 82.1 (100), 83.1 (13), 69.0 (15), 68.1 (87), 67.1

(20), 56.1 (18), 55.0 (17), 54.0 (23), 53.0 (16), 44.0 (26), 43.0 (28),

42.0 (19), 41.0 (47), 40.0 (20), 39.0 (48). HRMS-EI (m/z): [M⁺] calcd

for C₈H₁₅N, 125.1205; found, 125.1204.

N-Boc-2-[(E)-prop-1-enyl]piperidine (Boc-6a). ¹H NMR (500

MHz, CDCl₃): δ 5.50 (d of quartet, 16.0 Hz, 6.0 Hz, 1H), 5.44 (dd,

16.0 Hz, 4.0 Hz, 1H), 4.73 (s, 1H), 3.92 (d, 13.0 Hz, 1H), 2.83 (dt, 2.5

Hz, 13.0 Hz, 1H), 1.70 (d, 5.5 Hz, 3H), 1.67-1.49 (m, 5H), 1.46 (s,

9H), 1.43-1.34 (m, 1H); ¹³C NMR (125.7 MHz, CDCl₃) δ 155.6, 129.6,

126.6, 79.3, 52.1, 39.9, 29.7, 28.7, 25.9, 19.7, 18.1. MS (rel abun-

dance): M⁺225.1 (1), 170.1 (10), 169.1 (100), 154.1 (73), 152.1 (27),

141.1 (15), 128.1 (22), 124.1 (61), 110.1 (33), 97.1 (46), 96.1 (11),

84.1 (16), 82.1 (28), 68.1 (17), 67.1 (13), 57.1 (97), 56.1 (13), 55.1

(22), 43.1 (10), 41.1 (47), 39.1 (17). HRMS-EI (m/z): [M⁺] calcd for

C₁₃H₂₃NO₂, 225.1729; found, 225.1729.

N-Boc-trans-2-methyl-5-propylpyrrolidine (trans-17). Trans:cis )

9:1 mixture, ¹H NMR (500 MHz, CDCl₃) δ 3.97-3.64 (m, 2H), 2.05-

1.76 (m, 3H), 1.61 (quartet, 6.0 Hz, 2H), 1.46 (s, 9H), 1.32-1.10 (m,

6H), 0.91 (t, 7.0 Hz, 3H); ¹³C NMR (125.7 MHz, CDCl₃) δ 154.2,

154.1, 78.9, 57.8, 57.6, 54.1, 53.1, 53.0, 36.4, 35.3, 30.7, 29.9, 28.8,

27.6, 26.6, 20.6, 20.2, 20.1, 19.8, 19.6, 14.4, 14.3. Both isomers exhibit

indistingishable mass spectra; MS (rel abundance): M⁺227.2 (1), 184.1

(16), 154.1 (16), 128.1 (100), 84.1 (84), 69.1 (10), 57.1 (83), 56.1 (10),

55.1 (14), 43.1 (11), 42.1 (11), 41.1 (50), 39.0 (14). HRMS-EI (m/z):

[M⁺] calcd for C₁₃H₂₅NO₂, 227.1886; found, 227.1888.

N-Cbz-2-[(E)-prop-1-enyl]piperidine (Cbz-6a). (Isolated by pre-

1

parative-scale method 1) H NMR (500 MHz, CDCl₃) δ 7.43-7.28

(m, 5H), 5.61-5.45 (m, 2H), 5.17 and 5.13 (AB quartet, 12.5 Hz, 2H),

4.84 (s, 1H), 4.03 (d, 13.0 Hz, 1H), 2.92 (t, 12.0 Hz, 1H), 1.70 (d, 4.5

(21) Presumably, two possible conformers (pseudoequatorial or pseudoaxial

propenyl) exist which interconvert slowly on the NMR time scale; therefore,

some peaks appear as a pair.

9

15882 J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003

Aminodienes Catalyzed by Organolanthanide Complexes

A R T I C L E S

cis-2-Methyl-6-[(E)-Prop-1-enyl]piperidine, (()-Pinidine (cis-

16a).^{11b,22 1}H NMR (500 MHz, CDCl₃): δ 5.56 (d of quartet, 15.3 Hz,

6.5 Hz, 1 H), 5.45 (ddd, 15.3 Hz, 6.8 Hz, 1.5 Hz, 1H), 3.05-3.02 (m,

1H), 2.68-2.62 (m, 1H), 1.78-1.74 (m, 1H), 1.65 (d, 6.0 Hz, 3H),

1.59-1.54 (m, 2H), 1.40-1.28 (m, 2H), 1.20-0.98 (m, 2H), 1.05 (d,

6.0 Hz, 3H); ¹³C NMR (125.7 MHz, CDCl₃) δ 135.3, 125.0, 59.6, 52.3,

34.0, 32.4, 24.8, 23.2, 18.0. MS (rel abundance): M⁺139.1 (35), 138.1

(18), 124.1 (100), 111.1 (21), 110.1 (20), 98.1 (23), 96.1 (64), 82.1

(56), 81.1 (39), 70.1 (22), 69.1 (13), 68.1 (54), 67.1 (20), 55.1 (20),

53.1 (12), 44.1 (30), 43.1 (13), 42.1 (21), 41.1 (33), 39.1 (20). HRMS-

EI (m/z): [M⁺] calcd for C₉H₁₇N, 139.1361; found, 139.1357.

N-Boc-cis-2-methyl-6-propylpiperidine, (()-N-Boc-dihydropini-

dine (cis-18).^{23 1}H NMR (500 MHz, CDCl₃) δ 4.31-4.28 (m, 1H),

4.08-4.04 (m, 1H), 1.69-1.24 (m, 10H), 1.46 (s, 9H), 1.16 (d, 7.5

Hz, 3H), 0.92 (t, 7.0 Hz, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ 155.4,

79.0, 50.4, 45.9, 37.6, 30.6, 28.9, 27.7, 21.1, 20.7, 14.6, 14.5. MS (rel

abundance): M⁺241.2 (0.1), 198.1 (10), 168.1 (8), 143.1 (8), 142.1

(100), 98.1 (46), 69.1 (8), 57.1 (40), 55.1 (10), 41.1 (21). HRMS-EI

(m/z): [M⁺] calcd for C₁₄H₂₇NO₂, 241.2042; found, 241.2042.

N-Boc-trans-2-methyl-6-propylpiperidine, (()-N-Boc-epidihydro-

pinidine (trans-18).^{24 1}H NMR (500 MHz, CDCl₃): δ 3.93-3.90 (m,

1H), 3.88-3.79 (m, 1H), 1.70-1.22 (m, 10H), 1.46 (s, 9H), 1.23 (d,

6.8 Hz, 3H), 0.91 (t, 7.2 Hz, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ

155.4, 78.9, 51.6, 47.2, 36.9, 28.9, 27.2, 23.5, 21.2, 20.6, 14.5, 14.1.

MS (rel abundance): [M - 43]⁺198.1 (7), 168.1 (7), 143.1 (8), 142.1

(100), 98.1 (54), 69.1 (8), 57.1 (62), 55.1 (11), 41.1 (23).

(br s, 3H), 0.95 (t, 7.0 Hz, 3H); ¹³C NMR (125.7 MHz, CDCl₃) δ 57.5,

45.0, 35.6, 28.4, 22.7, 22.5, 18.9, 14.0. Anal. Calcd for C₈H₁₈ClN: C,

25

58.70; H, 11.08; N, 8.56. Found: C, 58.59; H, 10.94; N, 8.42. [R]_D

) +3.2° (EtOH, c 0.61).

°C

Kinetic Studies of Hydroamination/Cyclization. In a typical

experiment, an NMR sample was prepared as described above (see

Typical NMR-Scale Catalytic Reaction) but maintained at -78 °C until

kinetic measurements were begun. The sample tube was then inserted

into the probe of the INOVA-500 spectrometer which had been

previously set to the appropriate temperature (T ( 0.2 °C; checked

with a methanol or ethylene glycol temperature standard). A long pulse

delay (8 s) was used during data acquisition to avoid saturation. The

reaction kinetics were usually monitored from intensity changes in one

of the conjugated olefinic resonances over three or more half-lives.

The substrate concentration, C, was measured from the olefinic peak

area, A_s, standardized to the area A_lof the free EH(TMS)₂(E ) N or

CH) formed as turnover commences. The EH(TMS)₂is present as a

result of quantitative protonolytic ligand cleavage during catalyst

generation. Usually, data collected up to 80% conversion could be

convincingly fit by least-squares to eq 3 where C_ois the initial

concentration of substrate (C_o) A_so/A_lo). The turnover frequency (h^-1

)

was calculated from the least-squares determined slope (m) according

to eq 4.

C ) mt + C_o

(3)

(4)

N_t(h^-1) ) -(60 min h^-1)m

Determination of Enantiomeric Excess and Absolute Configu-

ration. The enantiomeric excess values of entries 1 and 3 in Table 4

were determined by GC-MS analysis of the corresponding Mosher

amides²⁵of the hydrogenated products. The two diastereomers of the

(S)-Mosher amides of 2-propylpyrrolidine showed retention times of

33.5 and 34.2 min. The conditions were as follows: injector, 250 °C;

initial oven temperature, 40 °C for 3 min; 20 °C/min to 150 °C, hold

for 50 min; then 40 °C/min to 270 °C.

Results

The goal of this study was to further explore the scope and

selectivity of the organolanthanide-mediated intramolecular

hydroamination/cyclization reaction, searching for highly ste-

reoselective catalytic pathways general to heterocycle construc-

tion. First, the catalytic intramolecular hydroamination/cycliza-

tion of the aminodienes is described, including the scope of the

reaction, as well as the effects of varying substrate substituents,

metal center, and ancillary ligands. Next, diastereo- and enan-

tioselectivity are examined with an emphasis on alkaloid

synthetic applications. Finally, reaction kinetics and mechanistic

pathways are discussed, including rate laws, activation param-

eters, and their mechanistic implications.

Scope of Catalytic Aminodiene Hydroamination/Cycliza-

tion. Anaerobic cyclization of conjugated aminodienes²⁸medi-

ated by Cp′₂LnCH(TMS)₂(Cp′ ) η⁵-Me₅C₅),^16cCGCLnN-

(TMS)₂(CGC ) Me₂Si(η⁵-Me₄C₅)(^tBuN)),^8gor (S)-Me₂Si(OHF)-

(CpR*)SmN(TMS)₂(OHF ) η⁵-octahydrofluorenyl; Cp ) η⁵-

C₅H₃; R* ) (-)-menthyl)^9aprecatalysts proceeds with high

conversions and reasonably rapid turnover frequencies at 25 or

60 °C (Table 1). The reaction scope includes five- and six-

membered ring formation using primary and secondary amines,

as well as monosubstituted and 1,4-disubstituted dienyl groups.

The transformation exhibits very high regioselectivity.²⁹Thus,

2-substituted pyrrolidines (Table 1, entries 1-8, 13-16) and

piperidines (Table 1, entries 9-12) are formed via 5-exo and

6-exo cyclizations, respectively, and there is no evidence of

alternative 6- or 7-endo cyclizations. Products a/b are obtained

as major products (Table 1, entries 1-12) for terminal mono-

substituted dienes; however, products c/d predominate when 1,4-

disubstituted substrates are employed (Table 1, entries 13-16).

The values for the enantiomeric excess in entries 5-16 of Table 4

were determined by chiral stationary phase HPLC using a Regis (S,S)-

Whelk O1 column (i.d. ) 4.6 mm, length ) 250 mm, particle size )

5 µm) with a flow rate of 2.0 mL/min and hexane/ⁱPrOH (85:15) as

eluent.²⁶Racemic 6a (Table 1, entry 9) was used as a standard, and

two enantiomers of N-1-naphthoyl derivatives^26cof racemic 6a showed

retention times of 23.5 and 43.0 min. The products from the enantio-

selective hydroamination (Table 4, entries 5-12) showed a minor peak

at 23.5 min and major peak at 43.0 min. To assign the absolute

configuration of the enantiomers, Cbz derivative of 6a (Cbz-6a) was

hydrogenated (H₂, Pd/C, EtOH, rt, 1 h) and then treated with HCl (2M

in Et₂O) at 0 °C for 1 h to afford the HCl salt of 2-propylpiperidine

(25•HCl), Coniine•HCl, in a 94% two-step overall yield (Scheme 3).

25 °C

The specific rotation value for this product was found to be [R]_D

) +3.2° (EtOH, c 0.61). Compared to the known value [[R]_D^{20 °C}) +

5.2° (EtOH, c 1.0) for (2S)-(+)-Coniine•HCl],²⁷the configuration of

the major enantiomer of 2-[(E)-prop-1-enyl]piperidine (6a) was assigned

as R.

(2S)-2-Propylpiperidine, [(2S)-(+)-Coniine‚HCl](25‚HCl). 63% ee,

¹H NMR (500 MHz, CDCl₃) δ 9.51 (br s, 1H), 9.20 (br s, 1H), 3.45

(br s, 1H), 2.94 (br s, 1H), 2.81 (br s, 1H), 2.10-1.56 (m, 7H), 1.45

(22) Oppolzer, W.; Merifield, E. HelV. Chim. Acta 1993, 76, 957-962.

(23) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109-1117.

(24) Takahata, H.; Kubota, M.; Takahashi, S.; Momose, T. Tetrahedron:

Asymmetry 1996, 7, 3047-3054.

(25) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543-

2549.

(26) For examples of separation of racemates using an (S,S)-Whelk O1 column,

see: (a) Pirkle, W. H.; Welch, C. J. Tetrahedron: Asymmetry 1994, 5,

777-780. (b) Pirkle, W. H.; Welch, C. J.; Lamm, B. J. Org. Chem. 1992,

57, 3854-3860. For an example of separation of 2-substituted piperidines,

see: (c) Hyun, M. H.; Jin, J. S.; Lee, W. Bull. Korean Chem. Soc. 1997,

18, 336-339.

(28) See the Supporting Information for aminodiene substrate synthesis.

(29) Hydroamination/cylization of monosubstituted allenylamines affords mix-

tures of endo- and exo-cyclization regioisomers, whereas 1,3-disubstituted

allenylamines exclusively yield the exo-cyclization product. See ref 11b.

(27) Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H.-P. J. Am. Chem. Soc.

1983, 105, 7754-7755.

9

J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003 15883

A R T I C L E S

Hong et al.

Table 1. Results for Organolanthanide-Catalyzed Hydroamination/Cyclization of Conjugated Aminodienes

1

^aDetermined by H NMR. ^bPreparative-scale yield (entry 8) or that of Cbz carbamate (entry 10). ^cDetermined by H NMR and GC-MS or GC-MS

of Boc derivatives (entries 2, 3, 13, 14). ^dTurnover frequencies measured in C₆D₆with 3-11 mol % precatalyst. ^eCp′₂LaCH(TMS)₂as precatalyst.

^fCp′₂SmCH(TMS)₂as precatalyst. ^gCp′₂YCH(TMS)₂as precatalyst. ^hCGCSmN(TMS)₂as precatalyst. ⁱCGCYN(TMS)₂as precatalyst. ^j(S)-Me₂Si(Me₄Cp)

(CpR*)SmN(TMS)₂as precatalyst (R* ) (-)-menthyl). ^k(S)-Me₂Si(OHF) (CpR*)SmN(TMS)₂as precatalyst (R* ) (-)-menthyl).

In marked contrast to aminoallene hydroaminations in which

the Z double bond isomer (product b) is generally obtained as

a major product,¹¹good to high E double bond selectivity is

substitution of the carbon backbone (the Thorpe-Ingold effect,³¹

Table 1, entries 11 and 12) increases the N_t’s by approximately

1 order of magnitude, as also observed in aminoalkene

hydroamination.^8jNote that observed rates are comparable to

or greater than those of 4-pentenamine and 5-hexenamine

hydroamination/cyclization, despite increased substrate steric

encumbrance (Table 2).

Metal and Ancillary Ligand Effects on Catalytic Amino-

diene Hydroamination/Cyclization. In the case of amino-

alkene hydroamination/cyclization, both increasing the Ln³⁺

ionic radius and opening the metal coordination sphere by ansa-

fusion of the ancillary ligands (Cp′₂Ln- f Me₂SiCp′′₂Ln- or

Cp′₂Ln- f Me₂SiCp′′(CpR*)Ln-; Cp′′ ) C₅Me₄, R* )

(-)-menthyl)^32,9bincreases the turnover frequencies (N_t), pre-

sumably reflecting significant steric demands in the insertive

transition state (Scheme 1, step i).^8j,9b,32Catalyst structural effects

qualitatively similar to those in monosubstituted alkenylamine

1

observed with aminodienes. Monitoring the reactions by H

NMR shows that product ratio varies in only a minor way with

conversion, in most cases. However, for cyclization of dienes

9 and 11, the E/Z product distribution is time-dependent,

ultimately favoring thermodynamic products. For conversion

11 f 12, initial formation of 12a and subsequent isomerization

to 12c is observed in situ by ¹H NMR. Presumably, the doubly

activated benzylic/allylic C-H functionality in propenylpyrro-

lidine 12a is sufficiently acidic to facilitate isomerization (eq

5). As observed for aminoalkene, aminoalkyne, and aminoallene

(30) (a) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry, 4th ed.;

Kluwer Academic/ Plenum Publishers: New York, 2000; Part A, Chapter

3.9. (b) Illuminati, G.; Mandoline, L. Acc. Chem. Res. 1981, 14, 95-102.

(31) (a) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic

Compounds; Wiley-Interscience: New York, 1994; pp 682-684. (b) Kirby,

A. J. AdV. Phys. Org. Chem. 1980, 17, 183-278.

cyclizations, the ring-size dependence cyclization rates (N_t) for

aminodienes are 5 > 6, consistent with the classical, stereo-

electronically controlled cyclization process.³⁰Geminal dimethyl

(32) Jeske, G.; Schock, L. E.; Mauermann, H.; Swepston, P. N.; Schumann,

H.; Marks, T. J. J. Am. Chem. Soc. 1985, 107, 8103-8110.

9

15884 J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003

Aminodienes Catalyzed by Organolanthanide Complexes

A R T I C L E S

Table 2. Rate Comparison for Aminoalkene and Aminodiene

Hydroamination

selectivity, making the methodology particularly attractive for

pyrrolidine and pyrrolizidine alkaloid synthesis.¹¹

In the present study, the ring substituent diastereoselectivity

of aminodiene hydroamination/cyclization was investigated with

R-methyl aminodiene substrates (Table 3). Good diastereose-

lectivities (9:1 ) 2,5-trans/2,5-cis) are observed in the formation

of a 2,5-trans disubstituted pyrrolidine (13f 14) when CGC-

SmN(TMS)₂or Me₂Si(OHF)(CpR*)SmN(TMS)₂is used as a

catalyst (Table 3, entries 2 and 3). The relatively modest rate

and low selectivity with Cp′₂LaCH(TMS)₂for reaction 13f

14 (Table 3, entry 1) is rather exceptional considering that Cp′₂-

LaCH(TMS)₂consistently exhibits high N_t’s and good stereo-

selectivities with other aminodiene substrates. However, it was

previously observed that Cp′₂LaCH(TMS)₂is conspicuously

ineffective in the hydroamination/cyclization of a similar

substrate, 5-hepten-2-amine, at high temperatures, while it serves

as the most effective catalyst for cyclization of other amine-

tethered 1,2-disubstituted alkenes.^8cIn contrast, the present work

reveals excellent diastereoselectivity in formation of a 2,6-cis

disubstituted piperidine (Table 3, entries 4 and 5).³⁴Thus,

aminodiene 15 almost exclusively generates cis-2-methyl-6-[(E)-

prop-1-enyl]pyrrolidine (cis-16a) in high yield with reasonable

rate at room temperature. Note that entry 4 demonstrates a

concise, efficient synthesis of (()-pinidine³⁵with excellent

stereocontrols for both 2,6-cis substitution (cis/trans ) 178:1)

and trans-alkene geometry (E/Z/allyl ) 94:1:5).

^aOHF* ) (S)-Me₂Si(η⁵-octahydrofluorenyl)(CpR*), R*) (-)-menthyl.

^bReference 8l. ^cReference 9a. ^dEstimated from the reaction conditions

(catalyst mol % and reaction time) reported in ref 8c.

hydroamination are also operative in the present case. Thus,

for cyclization 1 f 2, N_tincreases substantially with increasing

metal ionic radius^8j,33(Cp′₂La- > Cp′₂Sm- > Cp′₂Y-, and

CGCSm- > CGCY-; Table 1, entries 1-3 and entries 4 and

5). Further examples of such dramatic N_tchange from La to

Sm are in the cyclization of 9 f 10 (N_t) 1.8 vs 0.02 h^-1at 60

°C; Table 1, entries 13 and 14), and 11 f 12 (N_t) 89 vs 2.3

h^-1at 60 °C; Table 1, entries 15 and 16). The kinetic effects of

the supporting π-ligation on N_tfor aminodiene hydroamination/

cyclization were also probed for transformation 1 f 2, and N_t

also generally increases with more open ligation [Me₂SiCp′′-

(CpR*) > Me₂Si(OHF)(CpR*) g CGC . Cp′₂; Table 1, entries

2, 4, 6, and 7]. Thus, aminodiene hydroamination/cyclization

experiences an appreciable acceleration in rate when larger ionic

radius Ln³⁺catalysts or more open ligations such as Me₂SiCp′′-

(CpR*) or Me₂Si(OHF)(CpR*) are employed.

Enantioselective hydroamination/cyclizations were investi-

gated by using the C₁-symmetric chiral organolanthanocene

catalysts, (S)-Me₂SiCp′′(CpR*)LnE(TMS)₂(Ln ) Sm, Y; E )

N, CH; R* ) (-)-menthyl)^9b,cand (S)-Me₂Si(OHF)(CpR*)-

SmN(TMS)₂,^9aas well as the recently developed C₂-symmetric

bisoxazoline catalyst, (4R,5S)-Ph₂BoxLa[N(TMS)₂]₂(Table 4).³⁶

Diastereo- and Enantioselectivity in Aminodiene Hy-

droamination/Cyclization. Cyclization of 5-hexen-2-amine has

been studied in detail for diastereoselectivity effects in ami-

noalkene hydroamination/cyclization (eq 6). It was found that

The enantioselectivities of the reactions were assayed by chiral

HPLC analysis of the 1-naphthoyl amide derivatives^26cof the

crude products or hydrogenated products if the reaction produced

>5% minor isomer. Distinctive color changes associated with

catalytic initiation and termination as in hydroamination of other

amino-unsaturation systems^8j,10c,11bwere found to be very useful

for qualitatively monitoring the course of the reaction, especially

at 0 °C. Thus, the original orange solution of the paramaganetic

the 2,5-trans:2,5-cis ratio is highly dependent on lanthanide ion

size, π-ancillary ligation, reaction temperature, and added

exogenous ligands such as n-propylamine.^8jFor example, Cp′₂-

Ln-/Me₂SiCp′′₂Ln- (Ln ) Nd, Sm) precatalysts afford only

modest diastereoselection (1:1-5:1, trans/cis) at 25 °C, whereas

CGCLn (Ln ) Nd, Sm)^8gand chiral catalysts Me₂SiCp′′(CpR*)-

Ln- (Ln ) Nd, Sm, R* ) (-)-menthyl)^9bexhibit greatly

improved diastereoselectivities (10:1 trans/cis and >95% trans,

respectively). In contrast, aminoallene hydroamination/cycliza-

tion mediated by Cp′₂Ln- catalysts proceeds, depending on the

substrate, with either exclusive 2,5-trans or 2,6-cis diastereo-

5

Sm³⁺(4f ) precatalyst, Me₂Si(OHF)(CpR*)SmN(TMS)₂, im-

mediately turns to the light yellow color upon substrate addition.

The resulting reaction solution reverts to the original color upon

aminodiene substrate consumption. In the case of heptadienyl

substrate 1 for pyrrolidine formation, the results indicate modest

selectivity (17-41% ee; Table 4, entries 1-4) at best, less than

(34) Relative stereochemistry confirmed by NOESY experiments and deriva-

tization.

(35) Kirihara, M.; Nishio, T.; Yokoyama, S.; Kakuda, H.; Momose, T.

Tetrahedron 1999, 55, 2911-2926 and references therein.

(36) (a) Hong, S.; Ryu, J-.S.; Tian, S.; Metz, M. V.; Marks, T. J. Abstracts of

Papers; communicated in part at the 224th National ACS Meeting, Boston,

MA; August 2002; American Chemical Society: Washington, DC, 2002;

abstract INOR 668. (b) Hong, S.; Tian, S.; Metz, M. V.; Marks, T. J. J.

Am. Chem. Soc., in press.

(33) 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. See: Shannon, R. D. Acta Crystallogr., Sect. A 1976, A32,

751-767.

9

J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003 15885

A R T I C L E S

Hong et al.

Table 3. Diastereoselectivity in the Organolanthanide-Catalyzed Hydroamination/Cyclization of Conjugated Aminodienes^a

^aStarting aminodienes completely consumed as judged by ¹H NMR (>95% conversion). ^bDetermined by GC-MS ratio of corresponding hydrogenated

Boc derivatives. ^cTurnover frequencies measured in C₆D₆with 5 mol % precatalyst. ^dCa. 10% allyl products formed. ^eCp′₂LaCH(TMS)₂as precatalyst.

^f(S)-Me₂Si(OHF)(Cp*)SmN(TMS)₂as precatalyst. ^gCGCSmN(TMS)₂as precatalyst. ^hCis/trans ) 178:1; alkene isomer ratio (E/Z/allyl ) 94:1:5).

Table 4. Enantioselective Cyclization of Aminodienes^a

chiral

precatalyst

temp

(°C)

c

entry

substrate

product (ratio)^b

solvent

benzene-d₆

N, h^-1

%ee (config)^d

t

1

2

3

4

1

2a/b (93:7)

2a/b (98:2)

2a/b (63:37)

OHF*Sm

Cp*Sm

Cp*Y

12

74

0.09

3.0

25

23

25

23

25^e

41

Ph₂BoxLa

17^e

5

6

7

8

9

10

11

12

13

5

6a/b (97:3)

6a/b (96:4)

6a/b (95:5)

6a/b (97:3)

6a/b (98:2)

6a/b (41:59)

OHF*Sm

Cp*Sm

benzene-d₆

toluene-d₈

0.11

0.04

0.09

25

0

25

0

25

0

25

60

63 (R)

64 (R)

69 (R)

64 (R)

71 (R)

65 (R)

37 (R)

54^e(R)

cyclohexane-d₁₂

methylcyclohexane-d₁₄

pentane

∼0.08

0.1

0.6

benzene-d₆

Ph₂BoxLa

14

15

16

7

8a/b (96:4)

8a/b (93:7)

8a/b/c (39:57:4)

OHF*Sm

Ph₂BoxLa

benzene-d₆

cyclohexane-d₁₂

benzene-d₆

1.7

1.4

25

0

23

19

24

45^e

^aConditions: 4-7 mol % or 20 mol % (0 °C reactions) catalyst, ∼0.6 mL of solvent. ^bDetermined by GC-MS. ^cFor the major isomer, determined by

chiral HPLC analysis. Measured ee’s vary only weakly with conversion. ^dDetermined by optical rotation of the HCl salt of the hydrogenated product.

Absolute configuration of major isomer. ^eDetermined by chiral HPLC analysis of hydrogenated product.

that observed in homologous pentenamine cyclization with the

same catalysts (40-69% ee; Table 5, entries 1-4).^9,36Octadi-

enamine cyclizations 5 f 6a/b display higher selectivity, with

the Me₂Si(OHF)(CpR*)Sm catalyst exhibiting the highest ee

of 71% (Table 4, entries 5-13). This enantioselectivity repre-

sents a substantial improvement in the formation of 2-substituted

piperidines versus the homologous aminoalkene cyclization

mediated by the same OHF catalyst, affording only 10% ee at

60 °C (Table 5, entry 5). For cyclization 5 f 6a/b mediated by

the OHF catalyst in benzene at 25 °C, enantiomeric excess was

assayed at different conversions, and measured ee’s were found

to vary only weakly with conversion (64% ee at 25% conver-

sion, 64% ee at 47% conversion, 65% ee at 70% conversion).

In an effort to further enhance ee’s, several other nonpolar

solvents (toluene, cyclohexane, methylcyclohexane, and pentane)

were employed but only minor solvent effects on enantioselec-

tivity were observed. Decreasing the temperature from 25 °C

to 0 °C improves ee’s by ∼5%. When exogenous chiral Lewis

base ligands are added, enantioselectivity remains virtually the

same or increases only slightly, while reaction rates are

significantly depressed (Table 6). Gem-dimethyl substitution on

the substrate carbon backbone enhances cyclization rates as

expected;³¹however, the enantioselectivity is diminished (Table

4, entries 14-16). Scheme 3 illustrates how the absolute

configuration of 6a/b was determined. Note that the natural

product (+)-coniine•HCl³⁷is efficiently synthesized from

prochiral aminodiene substrate 5 in an essentially two-step

sequence in very high isolated yield. Although the enantiose-

lection in the key hydroamination/cyclization step is not

perfected yet with currently available chiral organolanthanide

catalysts, this example demonstrates the potential synthetic

(37) For the catalytic asymmetric synthesis of coniine via imine hydrosilylation,

see: Reding, M. T.; Buchwald, S. L. J. Org. Chem. 1998, 63, 6344-6347

and references therein for other recent syntheses.

9

15886 J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003

Aminodienes Catalyzed by Organolanthanide Complexes

A R T I C L E S

Table 5. Enantioselective Cyclization of Homologous Aminoalkenes

chiral

precatalyst

temp

(°C)

entry

substrate

product

solvent

N, h^-1

% ee^a(config)^b

ref

t

1

2

3

4

19

20

OHF*Sm

Cp*Sm

(R)-Cp*Y

Ph₂BoxLa

benzene-d₆

pentane

2.6

33

25

23

46 (+)

62 (+)

69 (+)

40 (-)

9a

9b

43

benzene-d₆

0.09

6.6

5

21

22

OHF*Sm

benzene-d₆

60

10 (+)

9a

6

7

8

23

24

OHF*Sm

Cp*Sm

Ph₂BoxLa

benzene-d₆

pentane

benzene-d₆

0.6

2

4.0

25

60

41 (+)

15 (-)

56 (+)

9a

9b

43

^aDetermined by GC-MS of the corresponding Mosher amide (entries 1, 5, 6), ¹⁹F NMR of the Mosher amide (entries 2, 3, 7), or chiral HPLC analysis

(entries 4, 8). ^bDetermined by optical rotation.

Table 6. Effects of Chiral Lewis Base Additives on Enantioselective Aminodiene Hydroamination/Cyclization

Scheme 3. Synthesis of (2S)-(+)-Coniine•HCl; Determination of the Absolute Configuration of 6a

utility of the enantioselective hydroamination routes to 2-sub-

stituted piperidines.

normalized to the ¹H resonance of the stoichiometrically

generated CH₂(TMS)₂reaction byproduct (δ ≈ 0.2 ppm). Figure

2A presents kinetic data for this reaction (typical of many runs),

which indicate that the reaction rate is zero order in substrate

concentration over ∼3 half-lives, in analogy to the hydroami-

nation/cyclization of aminoalkenes,^8jaminoalkynes,^10cand

aminoallenes.^11bAnother example of such zero-order behavior

is in the cyclization 15f 16a/b using the precatalyst CGCSmN-

(TMS)₂in benzene-d₆at 60 °C (Figure 2B and Table 3, entry

Kinetic and Mechanistic Studies of Aminodiene Hy-

droamination/Cyclization. A kinetic study of the 1f 2a/b

1

cyclization was undertaken by in situ H NMR spectroscopy.

The reaction of a 40-80-fold molar excess of (4E,6)-heptadien-

1-amine (1) with Cp′₂LaCH(TMS)₂was monitored with constant

catalyst concentration until complete substrate consumption. The

decrease of one of the diene olefinic peaks (δ ≈ 6.0 ppm) was

9

J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003 15887

A R T I C L E S

Hong et al.

Figure 2. (A) Ratio of substrate to lanthanide concentration as a function

of time for the hydroamination/cyclization of (4E,6)-heptadien-1-amine (1)

using the precatalyst Cp′₂LaCH(TMS)₂in benzene-d₆at 25 °C. (B)

Normalized ratio of substrate to lanthanide concentration as a function of

time for the hydroamination/cyclization of (6E,8)-nonadien-2-amine (15)

using the precatalyst CGCSmN(TMS)₂in benzene-d₆at 60 °C.

Figure 3. (A) Normalized ratio of substrate to lanthanide concentration as

a function of time for the hydroamination/cyclization of (4E,6)-heptadien-

1-amine (1) using the precatalyst CGCSmN(TMS)₂in benzene-d₆at 25

°C. (B) Normalized ratio of substrate to lanthanide concentration as a

function of time for the hydroamination/cyclization of (5E,7)-octadien-1-

amine (5) using the precatalyst Cp′₂LaCH(TMS)₂in benzene-d₆at 25 °C.

6). Indeed, many aminodiene cyclizations exhibit zero-order

kinetics in substrate (Table 1, entries 1-3, 6, 7, 13-16; Table

3, entries 2, 5, 6). However, deviations from the zero-order

linearity are also observed in some cases (Figure 3). Two

variants are observed; either the rate of the aminodiene

cyclization begins to decrease (Figure 3A) or increase (Figure

3B) after about the first half-life. The first type of deviation

can be modeled by competitiVe product inhibition^8j,9b,38(Table

1, entries 4 and 8; Table 3, entries 1, 3, 4), whereas the second

type can be interpreted as substrate self-inhibition (Table 1,

entries 9-12). Since the first type of kinetic plot can be fit very

well over a broad range of conversions with an exponential

function (Figure 3A), it is not straightforward to distinguish

between zero-order kinetics with substantial competitive product

inhibition and true first-order kinetics by this integrated rate

law method alone. Therefore, the half-life method in conjunction

with the initial rate method³⁹was employed to determine the

reaction order in aminodiene substrate concentration for the

transformation 1f 2a/b using the CGCSmN(TMS)₂precatalyst.

Three new reactions starting with different initial substrate

concentrations were analyzed by ¹H NMR. Instead of real half-

life points for each run, projected half-life points from the first

20% conversion data were taken and plotted versus initial

substrate concentration because of possible product participation

in reaction rate (Figure 4A). Figure 4A shows that the half-life

points increase linearly with initial substrate concentration,

clearly indicating zero-order kinetics in [substrate] (eqs 7 and

8).

-d[S]

dt

) k[S]ⁿ

(7)

(8)

(9)

[S]_o

n ) 0:

n ) 1:

[S]_t) [S]_o-kt

[S]_t) [S]_oe^-kt

t_1/2

)

2k

ln2

k

t_1/2

(2^n-1- 1)

In general (n * 1),

t_1/2

)

(10)

n-1

k(n - 1) [S]_o

To further test the product inhibition hypothesis, an additional

aliquot of 1 was added to the same reaction mixture, after the

1

initial cyclization 1f 2a/b was complete by H NMR (Figure

5). The measurement shows more severe inhibition (deviation

from zero-order kinetics) in the second data set, where

substantial concentrations of product 2a/b are now present.

Therefore, the observed deviation from linearity likely reflects

product participation. Further discussion of this mechanistic

implication is deferred to the Discussion section.

When the initial concentration of aminodiene is held constant

and the concentration of the precatalyst is varied over a 10-

fold range, a plot of reaction rate versus precatalyst concentration

(Figure 6A) and a plot of ln(rate) versus ln[catalyst] (van’t Hoff

plot, slope ) reaction order, Figure 6B) indicates the reaction

(38) Organolanthanide-catalyzed hydrophosphinations exhibit similar but more

pronounced kinetic inhibition effects, depending upon the steric bulk of

the product. See: Douglass, M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem.

Soc. 2001, 123, 10221-10238.

(39) Steinfeld, J. I.; Francisco, J. S.; Hase, W. L. Chemical Kinetics and

Dynamics 2nd ed.; Prentice Hall: New Jersey, 1999; pp 1-13.

9

15888 J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003

Aminodienes Catalyzed by Organolanthanide Complexes

A R T I C L E S

Figure 4. (A) Plot of half-life points projected from the initial 20%

conversion as a function of initial substrate concentration for the hydroami-

nation/cyclization of (4E,6)-heptadien-1-amine (1) using the precatalyst

CGCSmN(TMS)₂in benzene-d₆at 25 °C. The line is the least-squares fit

to the data points with y-intercept ) 0. (B) Half-life method plot for the

hydroamination/cyclization of (4E,6)-heptadien-1-amine (1) using the

precatalyst CGCSmN(TMS)₂in benzene-d₆at 25 °C. The line is the least-

squares fit to the data points. The slope of the line equals 1 - n (n )

reaction order).

Figure 6. (A) Determination of reaction order in lanthanide concentration

for the hydroamination/cyclization of (4E,6)-heptadien-1-amine (1) using

the precatalyst Cp′₂LaCH(TMS)₂in benzene-d₆at 25 °C. (B) van’t Hoff

plot for the hydroamination/cyclization of (4E,6)-heptadien-1-amine (1)

using the precatalyst Cp′₂LaCH(TMS)₂in benzene-d₆at 25 °C. The lines

are least-squares fits to the data points.

Discussion

Substituent, Metal, and Ancillary Ligand Effects on

Catalytic Activity. Rates of aminodiene cyclization are far more

rapid than those for internal alkene hydroamination^8cand are

comparable to or even faster than those for terminal alkene

hydroamination^8j(Table 2). This ordering can be viewed as a

substituent group effect on the rate of aminoalkene hydroami-

nation, and N_tincreases in the order Me , H < vinyl for Cp′₂-

La- or Me₂Si(OHF)(CpR*)Sm- catalyzed reactions. Further-

more, N_talso varies with terminal dienyl group substituent in

the order of Me , H < Ph (Cp′₂Sm- catalyst, Table 1, entries

2, 14, 16) or Me , Ph < H (Cp′₂La- catalyst, Table 1, entries

1, 13, 15) for cyclization 1 f 2. These two substituent effects

qualitatively confirm the proposed transition state electronic

demand model (C).⁴²Similar substituent effects were previously

proposed for aminoalkyne cyclization^10cand explained by

assuming an analogous structure (D).

Figure 5. Normalized ratio of substrate to lanthanide concentration as a

function of time for the hydroamination/cyclization of (4E,6)-heptadien-1-

amine (1) using the precatalyst CGCSmN(TMS)₂in benzene-d₆at 25 °C.

The deviation from zero-order kinetics is ascribed to competitive inhibition

byproduct (see text).

to be the first-order in [catalyst]. Overall, the empirical rate law

can then be expressed as in eq 11 and is identical to that for

organolanthanide-catalyzed aminoalkene,^8jaminoalkyne,^10cand

aminoallene^11bhydroamination/cyclization.

ν ) k[substrate]⁰[Ln]¹

(11)

Variable temperature kinetic measurements were also carried

out for the 1f 2a/b cyclization mediated by Cp′₂LaCH(TMS)₂

and indicate the reaction to be zero-order in substrate concentra-

tion over a greater than 30 °C temperature range (Figure 7A).

Standard Arrhenius and Eyring kinetic analyses⁴⁰(Figure 7B)

afford the activation parameters E_a) 11.0 (0.4) kcal/mol, ∆H^‡

) 10.4 (0.4) kcal/mol, and ∆S^‡) -32.7 (1.2) cal/K mol.⁴¹

Metal and ancillary ligation effects on aminodiene hydroami-

nation qualitatively parallel those for aminoalkene hydroami-

(40) Benson, S. W. Thermochemical Kinetics, 2nd ed.; Wiley: New York, 1986;

pp 8-10.

(41) Parameters in parentheses represent 3σ values derived from the least-squares

fit.

9

J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003 15889

A R T I C L E S

Hong et al.

Figure 8. Plausible transition states for diastereoselective aminodiene

hydroamination/cyclization.

slightly different kinetic behavior (more pronounced competitive

product inhibition) in aminodiene cyclization, factors other than

steric (e.g., a greater number of coordinated amine ligands

arrayed about the metal center, depressing otherwise more rapid

reaction rates) may also contribute to the activity of CGCSm-

complexes.

Overall, conjugated aminodiene cyclizations appear to take

advantage of electronic effects (stabilization of electronic

demands) in the insertive transition state, leading to rate

enhancement. However, the turnover-limiting olefin insertion

step is even more sterically demanding than in aminoalkene

cyclizations.

Diastereo- and Enantioselectivity of Aminodiene Hy-

droamination/Cyclization. Good to excellent diastereoselec-

tivities are observed in 2,5-trans-disubstituted pyrrolidine and

2,6-cis-disubstituted piperidine cyclizations. The high diaste-

reoselectivities can be rationalized by assuming chairlike

transition states in which methyl and diene units occupy

thermodynamically more stable equatorial positions (minimal

1,3-diaxial interactions; Figure 8). In addition, the depicted

stereoselection model does not exhibit any unfavorable non-

bonding interactions between substrate and catalyst, which also

can affect the stereochemical outcome. Therefore, this model

accounts well for the observed diastereoselectivity.

Figure 7. (A) Normalized ratio of substrate to lanthanide as a function of

time and temperature for the hydroamination/cyclization of (4E,6)-heptadien-

1-amine (1) using the precatalyst Cp′₂LaCH(TMS)₂in benzene-d₆. (B)

Eyring plot for the hydroamination/cyclization of (4E,6)-heptadien-1-amine

(1) using the precatalyst Cp′₂LaCH(TMS)₂in benzene-d₆. The lines are

least-squares fits to the data points.

nation/cyclization.^8jN_tincreases with larger lanthanide ionic

radii and approximately with more open ligation. However, note

that N_tvaries much more dramatically with subtle changes in

metal ionic radius than in other catalytic systems. For example,

aminoalkene hydroamination exhibits a change of ∼10³× that

from La³⁺f Lu³⁺for the cyclization of 2,2-dimethyl-4-penten-

1-amine (eq 12), whereas the present catalytic system exhibits

>10³× change from La³⁺f Y³⁺(Table 1, entries 1-3),

arguing for a more sterically demanding transition state in the

turnover-limiting step. To judge relative coordinative openness

The steric demands of the putative η³-allyl intermediate

greatly influence the stereochemical outcome of enantioselective

aminodiene hydroamination/cyclization. Compared with ho-

mologous aminoalkene cyclization (Tables 4 and 5),⁹enanti-

oselectivity decreases ca. 20-40% for five-membered ring

formation (Table 4, entries 1-4 vs Table 5 entries 1-4),

whereas it increases substantially, from 10% to 63%, for six-

membered ring formation (Table 4, entries 5-13 vs Table 5,

entry 5). Interestingly, these trends are qualitatively similar to

those observed when ancillary ligand steric demands are

increased from Me₂SiCp′′(CpR*)Sm-^9bto Me₂Si(OHF)(CpR*)-

Sm-^9a(Table 5, entries 1 and 6 vs entries 2 and 7). In marked

contrast, additional installation of a gem-dimethyl group, which

was crucial for improved enantioselectivity in piperidine forma-

tion for aminoalkene hydroamintion with Me₂Si(OHF)(CpR*)-

Sm-^9a(Table 5, entry 6 vs entry 5), actually decreases ee values

in aminodiene cyclization (Table 4, entries 14-16). No simple

model is available at present to correlate substrate architectural

in closely related metallocene ligand structures, the centroid-

metal-centroid/amido angles are often compared. Thus, chelating

ancillary ligands such as Me₂SiCp′′(CpR*) ( ) 121° for SmN-

(TMS)₂),^9bMe₂Si(OHF)(CpR*) ( ) 122° for YN(TMS)₂),^9a

Me₂SiCp′′₂( ) 122° for NdCH(TMS)₂),³²and Me₂SiCp′′-

^tBuN) ( ) 95° for SmN(TMS)₂)^8gare more open than Cp′₂

(

) 134° for NdCH(TMS)₂).^16cFor cyclization 1 f 2, N_t

increases ∼10²× that from Cp′₂to the Me₂SiCp′′(CpR*)

ancillary ligand. However, the relative reactivity order between

the Me₂Si(OHF)(CpR*) and CGC ligand frameworks varies with

substrate, and sometimes Me₂Si(OHF)(CpR*) exhibits slightly

greater N_tvalues, although CGC ligation is generally considered

to be more open. Since the CGCSm- catalyst tends to exhibit

(42) Methyl substitution leads to a destabilization of the proposed transition

state C relative to R ) H or Ph; however, a reversed H versus Ph substituent

effect for two different lanthanide catalysts appears to imply competing

steric effects as well.

9

15890 J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003

Aminodienes Catalyzed by Organolanthanide Complexes

A R T I C L E S

Scheme 4. Mechanistic Scenarios for

Organolanthanide-Catalyzed Hydroamination

features with enantiomeric excess in these cyclizations. The

preliminary studies with chiral Lewis base additives (BINAP⁴³

and Pfaltz’s P,N ligand⁴⁴) reveal that cyclization rates are

moderately depressed while ee’s remain virtually unchanged,

regardless of additive stereochemistry. This can be interpreted

as indicating that the additive molecules are likely coordinated

to the lanthanide center in the resting state but must dissociate/

be displaced for the sterically demanding insertion process to

occur in cyclization 5 f 6. This scenario will be discussed

further in the following section.

Although the enantiomeric excess values presented here still

require improvement, the present results constitute another

important step forward to general enantioselective hydroami-

nation, potentially one of the most efficient and elegant ways

of constructing chiral amine molecules from prochiral unacti-

vated alkenes.

Kinetics and Mechanism of Aminodiene Hydroamination/

Cyclization. The kinetic results for the transformation 1 f 2

catalyzed by Cp′₂LaCH(TMS)₂indicate zero-order rate depen-

dence on substrate concentration (Figure 2A) and first-order

dependence on catalyst concentration (Figure 6), similar to the

scenario for intramolecular aminoalkenes,^8jaminoalkynes,^10cand

aminoallene hydroamination/cyclizations.^11bThis result argues

that the turnover-limiting step in the present case involves

intramolecular CdC insertion into the LnsN bond (Scheme 2,

step i), followed by rapid protonolysis of the resulting LnsC

bond (Scheme 2, step ii).

However, despite the apparent kinetic similarities, a plot of

substrate concentration versus time occasionally departs from

the typical linearity (zero-order kinetics) after about the first

half-life, affording either depressed rates (seemingly first-order-

like kinetic behavior, Figure 3A)^8j,9b,38or rate acceleration

(Figure 3B). Rate depressions are generally associated with

CGCSm- catalyzed diene cyclizations at room temperature

(Table 1, entries 4 and 8; Table 3, entries 1, 3, 4), whereas rate

accelerations are typical of six-membered ring formation medi-

ated by more encumbered Cp′₂Ln- catalysts (Table 1, entries

9-12). Further investigations of the seemingly first-order kinetic

behavior using the half-life method in conjunction with the initial

rate method reveal that the initial rate is still zero-order in

substrate (Figure 4). In addition, a kinetic plot for the second

batch cyclization in the presence of the first batch cyclization

products clearly indicates more pronounced deviation as well

as a depressed reaction rate (Figure 5). These two experiments

suggest the observed rate depression is due to competitive

inhibition by product. It was previously observed,^8jand is

supported by much independent evidence,⁴⁵that variable

numbers of amine molecules are coordinated to the metal center

and that these significantly modulate the diastereoselectivity of

aminoalkene hydroamination/cyclization as well as influence

rates mainly via competition with substrate molecules for the

reaction centers. It has also been observed that the exchange

process rapidly permutes not only lanthanide amido and the

coordinated amine groups but also coordinated and free amines.

These processes are fast on the NMR time scale even at very

low temperatures (eq 13).^8jSince the free-coordinated amine

exchange process should be highly sensitive to the relative

coordinating propensity of individual substrate and product

amine molecules as well as to the nature of lanthanide metal

center as defined by ionic radius and ancillary ligation, the

deviation from zero-order substrate kinetic linearity is, in

principle, always possible depending upon the particular com-

bination of catalyst, substrate, and product.⁴⁶

On the other hand, rate accelerations or self-inhibition by

substrate (Figure 3B) may imply a mechanistic variant. Scheme

4 portrays the two most reasonable mechanistic scenarios

selected from those originally considered for Cp′₂Ln- catalyzed

hydroamination/cyclization with consideration of turnover-

limiting olefin insertion and the possibility of additional bound

(43) BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl: Noyori, R.; Takaya,

H. Acc. Chem. Res. 1990, 23, 345-350.

(44) Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis 1997, 1338-

(46) Since the free-coordinated amine exchange process in the Cp′₂Ln- metal

environment does not involve the secondary heterocyclic cyclization

products, it was previously argued that once cyclized, the 2-methyl

heterocyles do not effectively compete with substrate for the catalyst center

nor function as inhibitors under typical reaction conditions for Cp′₂Ln-

1345.

(45) For example, the X-ray crystal structure of Cp′₂LnNHCH₃(H₂NCH₃) and

variable temperature ¹H NMR spectroscopy of Cp′₂LnNHCH₃(H₂NCH₃)

were reported.^8jThe formation of amine-amido adducts was proposed to

explain hydroamination/cyclization rate laws,^8jeffects of exogeneous bases

on reaction rates and diastereoselection in formation of 2,5-dimeth-

ylpyrrolidine,^8jfacile intermolecular alkyne insertion competing favorably

with intramolecular insertion,^10aparamagnetic line broadening in the ¹H

NMR,^9band epimerization of chiral lanthanocene catalysts in the presence

of amines.^9a-cFor other related examples, see footnote 38 in ref 10a.

1

catalyzed aminoalkene hydroamination.^8jHowever, subsequent in situ H

NMR experiments with paramagnetic, more open Me₂SiCp′′(CpR*)Ln

catalysts (Ln ) Nd, Sm) reveal that the product resonances are often

broadened after ∼l half-life, which implies that the product heterocycles

are significantly involved in coordination to/amine exchange with the chiral

paramagnetic lanthanide amine-amido complexes.^9b

9

J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003 15891

A R T I C L E S

Hong et al.

Table 7. Activation Parameter Comparison for Intramolecular

Hydroamination/Cyclization Reactions

Figure 9. Plot of reaction time versus substrate concentration for the

hydroamination/cyclization of (5E,7)-octadien-1-amine (5) using the pre-

catalyst Cp′₂LaCH(TMS)₂in benzene-d₆at 25 °C.

‡

noalkene cyclization. Note that the lower E_avalue (derived

from the standard Arrehenius analysis) of aminodiene cyclization

versus aminoalkene cyclization provides an explanation for the

rate enhancement observed with the dienyl group versus terminal

olefin. However, care must be taken in direct comparison of

the aminodiene cyclization activation parameters with those for

aminoalkyne and aminoallene cyclization, because of the

disparities in lanthanide metal ionic radius effects on N_t.⁴⁸

Overall, the present results obtained from the kinetic studies

(rate law, activation parameters) and from factors affecting

cyclization rates (metal ion size, π-ancillary ligand, product ring

size, substrate substituent effects) support a mechanistic scenario

analogous to the established hydroamination/cylization mech-

anism (Scheme 2), although the presence and role of coordinat-

ing amine ligands in the more sterically sensitive and highly

organized transition state may also depend on specific reaction

conditions.

amines present at the metal center: (1) amine-free catalyst in

equilibrium with an amine adduct (turnover-limiting olefin

insertion) and (2) (a) concerted amine displacement from an

amine-amido complex in concert with turnover-limiting olefin

insertion or (b) permanent amine coordination during turnover-

limiting olefin insertion. In scenario 1, the amine adduct is in

equilibrium with the amine-free form, the precursor to turnover-

limiting olefin insertion. Kinetic analysis using standard steady-

state conditions in Cp′₂LnNHR⁴⁷yields the rate law of eq 14,

in which [S] and [LnN₂] are the substrate and amine-amido

concentrations, respectively.

k

_prodk₁[LnN₂]

velocity )

(14)

k_-1[S] + k_prod

In the previous study of Cp′₂Ln- mediated aminoalkene

hydroamination, this scenario was reasonably excluded on the

basis that self-inhibition kinetics are not observed.^8jIn the

present study, a kinetic plot of aminodiene cyclization 5 f 6a/b

(Figure 3B) appears to follow the steady-state rate expression,

and this adherence is further substantiated when a time versus

[substrate] plot (Figure 9) is compared with the integrated form

of the rate expression, assuming time-independent [LnN₂] (eq

15).

Conclusions

The results presented here demonstrate that efficient orga-

nolanthanide-catalyzed intramolecular hydroamination/cycliza-

tion of amine-tethered 1,2-disubstituted alkenes is achieved using

readily accessible conjugated aminodienes. The catalytic reaction

proceeds cleanly at 25-60 °C with good rates, high regiose-

lectivities, and with electronic effects leading to significant rate

enhancements. Some features of the reaction parallel mono-

substituted aminoalkene hydroamination/cyclization, including

rate law and effects of lanthanide metal ionic radius and ancillary

ligation. Good to excellent diastereoselectivity is obtained in

2,5-trans-disubstituted pyrrolidine and 2,6-cis-disubstituted pi-

peridine syntheses. Aminodienes offer an enantioselective route

to 2-substituted azacycles. The reaction mechanism implicated

has both similarities to, and differences from, that defined for

aminoalkene hydroamination/cyclization.

k_-1

1

t )

[S]²-

[S] + constant

(15)

2k_prodk₁[LnN₂]

k₁[LnN₂]

Therefore, in the case of piperidine formation mediated by Cp′₂-

Ln- catalysts, additional coordinated amines must dissociate

to create a room for sterically demanding diene coordination/

insertion. The absence of additional amines in the transition state

of these octadienylamine cyclizations is further supported by

the aforementioned chiral additive studies, in which enantiomeric

access of the piperidine product is not affected by addition of

chiral Lewis base.

The present activation parameters for the transformation of

1 f 2a/b can be compared to the parameters for the hydroami-

nation/cyclization of aminoalkenes,^8jaminoalkynes,^10cand

aminoallenes^11b(Table 7). While the aminodiene cyclization

exhibits a lower enthalpic barrier than an analogous aminoalkene

cylization, the significantly larger magnitude of ∆S^‡(more

negative) suggests that the transition state is more highly

organized (greater loss of degrees of freedom) than in ami-

Acknowledgment. We thank NSF (CHE-0078998) for sup-

port of this research Dr. Y. Wu for help with NOESY

experiments, Prof. S. T. Nguyen and Mr. R. L. Paddock for

advice on chiral HPLC measurements, and Prof. F. E. McDonald

and Dr. M. R. Douglass for helpful suggestions.

Supporting Information Available: Substrate synthesis and

characterization data for all new compounds. This material is

available free of charge via the Internet at http://pubs.acs.org.

JA036266Y

(47) (a) Moore, J. W.; Pearson, R. G. Kinetics and Mechanisms, 3rd ed.;

Wiley: New York, 1981; pp 313-317 and references therein. (b) Segel, I.

H. Enzyme Kinetics; Wiley: New York, 1975; Chapters 1-3.

(48) N_tincreases in the order La³⁺< Sm³⁺< Y³⁺< Lu³⁺for aminoalkyne

cyclizations, whereas N_tincreases in the order La³⁺<Lu³⁺< Sm³⁺< Y³⁺

for aminoallene cyclizations.

9

15892 J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003

Article Doi

Intramolecular Hydroamination/Cyclization of Conjugated Aminodienes Catalyzed by Organolanthanide Complexes. Scope, Diastereo- and Enantioselectivity, and Reaction Mechanism

DOI: 10.1021/ja036266y

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Article abstract of DOI:10.1021/ja036266y

Full text of DOI:10.1021/ja036266y

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