Organolathanide-catalyzed regioselective intermolecular hydroamination of alkenes, alkynes, vinylarenes, di- and trivinylarenes, and methylenecyclopropanes. Scope and mechanistic comparison to intramolecular cyclohydroaminations

Article abstract of DOI:10.1021/ja035867m

Organolanthanide complexes of the type Cp′₂LnCH(SiMe ₃)₂ (Cp′ = η-Me₅C₅; Ln = La, Nd, Sm, Lu) and Me₂SiCp″₂LnCH(SiMe ₃)₂ (Cp″ = η⁵-Me₄C ₅; Ln = Nd, Sm, Lu) serve as efficient precatalysts for the regioselective intermolecular hydroamination of alkynes R′C≡CMe (R′ = SiMe₃, C₆H₅, Me), alkenes RCH=CH₂ (R = SiMe₃, CH₃CH₂CH ₂), butadiene, vinylarenes ArCH=CH₂ (Ar = phenyl, 4-methylbenzene, naphthyl, 4-fluorobenzene, 4-(trifluoromethyl)benzene, 4-methoxybenzene, 4-(dimethylamino)benzene, 4-(methylthio)benzene), di- and trivinylarenes, and methylenecyclopropanes with primary amines R″NH ₂ (R″ = n-propyl, n-butyl, isobutyl, phenyl, 4-methylphenyl, 4-(dimethylamino)phenyl) to yield the corresponding amines and imines. For R = SiMe₃, R = CH₂=CH lanthanide-mediated intermolecular hydroamination regioselectively generates the anti-Markovnikov addition products (Me₃SiCH₂CH₂NHR″, (E)-CH ₃CH=CHCH₂NHR″). However, for R = CH ₃CH₂CH₂, the Markovnikov addition product is observed (CH₃CH₂CH₂CHNHR″CH₃). For internal alkynes, it appears that these regioselective transformations occur under significant stereoelectronic control, and for R′ = SiMe ₃, rearrangement of the product enamines occurs via tautomerization to imines, followed by a 1,3-trimethylsilyl group shift to stable N-SiMe ₃-bonded CH₂=CMeN(SiMe₃)R″ structures. For vinylarenes, intermolecular hydroamination with n-propylamine affords the anti-Markovnikov addition product β-phenylethylamine. In addition, hydroamination of divinylarenes provides a concise synthesis of tetrahydroisoquinoline structures via coupled intermolecular hydroamination/subsequent intramolecular cyclohydroamination sequences. Intermolecular hydroamination of methylenecyclopropane proceeds via highly regioselective exo-methylene C=C insertion into Ln-N bonds, followed by regioselective cyclopropane ring opening to afford the corresponding imine. For the Me₂SiCp″₂Nd-catalyzed reaction of Me ₃SiC≡CMe and H₂NCH₂CH₂CH ₂CH₃, ΔH? = 17.2 (1.1) kcal mol^-1 and ΔS? = -25.9 (9.7) eu, while the reaction kinetics are zero-order in [amine] and first-order in both [catalyst] and [alkyne]. For the same substrate pair, catalytic turnover frequencies under identical conditions decrease in the order Me₂SiCp″₂NdCH(SiMe ₃)₂ > Me₂SiCp″ ₂SmCH(SiMe₃)₂ > Me₂SiCp″ ₂LuCH(SiMe₃)₂ > Cp′ ₂SmCH(SiMe₃)₂, in accord with documented steric requirements for the insertion of olefinic functionalities into lanthanide-alkyl and -heteroatom σ-bonds. Kinetic and mechanistic evidence argues that the turnover-limiting step is intermolecular C=C/C≡C bond insertion into the Ln-N bond followed by rapid protonolysis of the resulting Ln-C bond.

Full text of DOI:10.1021/ja035867m

Published on Web 09/23/2003
Organolathanide-Catalyzed Regioselective Intermolecular
Hydroamination of Alkenes, Alkynes, Vinylarenes, Di- and
Trivinylarenes, and Methylenecyclopropanes. Scope and
Mechanistic Comparison to Intramolecular
Cyclohydroaminations
Jae-Sang Ryu, George Yanwu Li,† and Tobin J. Marks*
Contribution from the Department of Chemistry, Northwestern UniVersity,
EVanston, Illinois 60208-3113
Received April 30, 2003; E-mail: t-marks@northwestern.edu
Abstract: Organolanthanide complexes of the type Cp′2LnCH(SiMe3)2 (Cp′ ) η5-Me5C5; Ln ) La, Nd, Sm,
Lu) and Me2SiCp′′2LnCH(SiMe3)2 (Cp′′ ) η5-Me4C5; Ln ) Nd, Sm, Lu) serve as efficient precatalysts for
the regioselective intermolecular hydroamination of alkynes R′CtCMe (R′ ) SiMe3, C6H5, Me), alkenes
RCHdCH2 (R ) SiMe3, CH3CH2CH2), butadiene, vinylarenes ArCHdCH2 (Ar ) phenyl, 4-methylbenzene,
naphthyl, 4-fluorobenzene, 4-(trifluoromethyl)benzene, 4-methoxybenzene, 4-(dimethylamino)benzene,
4-(methylthio)benzene), di- and trivinylarenes, and methylenecyclopropanes with primary amines R′′NH2
(R′′ ) n-propyl, n-butyl, isobutyl, phenyl, 4-methylphenyl, 4-(dimethylamino)phenyl) to yield the corresponding
amines and imines. For R ) SiMe3, R ) CH2dCH lanthanide-mediated intermolecular hydroamination
regioselectively generates the anti-Markovnikov addition products (Me3SiCH2CH2NHR′′, (E)-CH3CHdCHCH2-
NHR′′). However, for R ) CH3CH2CH2, the Markovnikov addition product is observed (CH3CH2CH2-
CHNHR′′CH3). For internal alkynes, it appears that these regioselective transformations occur under
significant stereoelectronic control, and for R′ ) SiMe3, rearrangement of the product enamines occurs via
tautomerization to imines, followed by a 1,3-trimethylsilyl group shift to stable N-SiMe3-bonded CH2dCMeN-
(SiMe3)R′′ structures. For vinylarenes, intermolecular hydroamination with n-propylamine affords the anti-
Markovnikov addition product â-phenylethylamine. In addition, hydroamination of divinylarenes provides a
concise synthesis of tetrahydroisoquinoline structures via coupled intermolecular hydroamination/subsequent
intramolecular cyclohydroamination sequences. Intermolecular hydroamination of methylenecyclopropane
proceeds via highly regioselective exo-methylene CdC insertion into Ln-N bonds, followed by regioselective
cyclopropane ring opening to afford the corresponding imine. For the Me2SiCp′′2Nd-catalyzed reaction of
Me3SiCtCMe and H2NCH2CH2CH2CH3, ∆Hq ) 17.2 (1.1) kcal mol-1 and ∆Sq ) -25.9 (9.7) eu, while the
reaction kinetics are zero-order in [amine] and first-order in both [catalyst] and [alkyne]. For the same
substrate pair, catalytic turnover frequencies under identical conditions decrease in the order Me2SiCp′′2-
NdCH(SiMe3)2 > Me2SiCp′′2SmCH(SiMe3)2 > Me2SiCp′′2LuCH(SiMe3)2 > Cp′2SmCH(SiMe3)2, in accord
with documented steric requirements for the insertion of olefinic functionalities into lanthanide-alkyl and
-heteroatom σ-bonds. Kinetic and mechanistic evidence argues that the turnover-limiting step is
intermolecular CdC/CtC bond insertion into the Ln-N bond followed by rapid protonolysis of the resulting
Ln-C bond.
Introduction
Carbon-heteroatom bond-forming reactions involving olefins
and alkynes are important synthetic transformations in organic
chemistry, and the direct addition of amines to such bonds is a
conspicuously challenging and highly desirable process.1 The
simple catalytic addition of an N-H bond to C-C unsaturation,
the hydroamination reaction, offers an efficient synthetic route
to primary, secondary, and tertiary amines, imines, and enam-
ines, by converting readily accessible alkenes and alkynes into
desirable, more highly substituted nitrogen-containing products
in a single step (e.g., eqs 1 and 2). The hydroamination of
alkynes1a,b (eq 1) affords relatively reactive enamines and imines,
which can be used for further synthetic manipulations, while
† Current address: CombiPhos Catalysts, Inc., Princeton, NJ 08542-0220.
9
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J. AM. CHEM. SOC. 2003, 125, 12584-12605
10.1021/ja035867m CCC: $25.00 © 2003 American Chemical Society

Organolanthanide-Catalyzed Hydroamination
A R T I C L E S
the hydroamination of alkenes directly provides a convenient
access to stable saturated amines (eq 2). Although catalytic
intermolecular homogeneous hydroamination of alkynes1a,b
mediated by transition metals has progressed substantially in
the last several years, the intermolecular hydroamination of
alkenes1 is generally recognized to be limited in scope due to
a high activation barrier, which plausibly arises from electrostatic
repulsion between the nitrogen lone pair electrons and the
electron-rich π-bond of the olefin. Moreover, these intermo-
lecular processes are generally much more difficult to achieve
and far less developed than intramolecular processes, which
are kinetically and thermodynamically favored.
ventional mechanisms involving metal imide (MdNR) com-
plexes, and less sterically demanding amines cannot be used
with alkynes or allenes, due to the formation of catalytically
inactive dimers. Analogous actinide complexes also exhibit
catalytic activity for terminal alkyne hydroamination in variable
yields (7-80%) and presumably operate via a similar mecha-
nism.13 Recently, notable progress in Ti-catalyzed14 intermo-
lecular hydroamination of alkynes with primary aryl- and
alkylamines has been achieved. Thus, Ti(NMe2)4,15 Ti(NMe2)2-
(dpma),16 and Ti-guanidinate complexes17 mediate hydroami-
nation of alkynes with arylamines, while with aniline and
sterically hindered amines react smoothly in the presence of
Cp2TiMe2, but with lower reactivity for less sterically hindered
n-alkylamines, due to unfavorable equilibria between Ti-imido
monomers, dimers, and bis(amides).18 Improved reactivity for
less sterically hindered n-alkylamines with bulky Cp*2TiMe2
has also been reported.19 However, to date, no example of
intermolecular alkene hydroamination has been reported for such
catalysts. In the past decade, significant progress has been made
with late- and early-transition-metal-mediated intermolecular
hydroamination of alkynes, but the intermolecular hydroami-
nation of alkenes and aliphatic amines still remains a challenge.1b
Traditionally, intermolecular hydroamination has required the
presence of alkali metals or metal hydrides at high temperatures
and pressures.2,3 More elegant processes have recently been
developed using early- and late-transition-metal catalysts. In
general, the advantage of late-transition-metal catalysts is their
greater tolerance of polar functional groups. The first successful
demonstration of this process was employed using Rh(III)4 and
Ir(III)5 complexes. More recently, Ru3(CO)126,7 and [Rh(cod)2]-
8
BF4 have been applied to the catalytic intermolecular hy-
droamination of aniline derivatives and terminal alkynes. In
addition, Pd complexes in the presence of acid additives also
mediate intermolecular alkyne hydroamination.9 Note also that
Pd-complex-catalyzed intermolecular hydroamination of viny-
larenes10 and dienes11 has been reported.
With regard to early transition metals,1a zirconocene-catalyzed
intermolecular hydroamination of alkynes and allenes with
aromatic amines has been extensively studied12 as the first
example of group IV metal mediated intermolecular hydro-
amination.1a Such transformations proceed via rather uncon-
In regard to organolanthanides,20 the remarkable kinetic
facility with which early lanthanide-alkyl and -heteroatom
bonds undergo intramolecular insertion of unactivated alkene,21
alkyne,22 allene,23 and diene24 functionalities (e.g., eqs 3 and
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A R T I C L E S
Ryu et al.
4; L2 ) (η5-Me5C5)2, Me2Si(η5-Me4C5)2; X ) NH, NR; Ln )
ity, and generality of organolanthanide-catalyzed intermolecular
alkene and alkyne hydroamination are not fully known. To
characterize the nature of organolanthanide-catalyzed intermo-
lecular alkene and alkyne hydroamination, we have undertaken
a detailed study of catalytic scope including aliphatic olefin,
butadiene, styrenic olefin, and methylenecyclopropanes. In
addition, we have investigated the regioselectivity, substrate
substituent effects, catalytic ancillary ligand and metal ion size
effects, kinetics, and mechanism, all of which are described
herein.
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 (10-6 Torr) 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 column34 and a
Davison 4Å molecular sieve column. All solvents were distilled before
use under dry nitrogen over appropriate drying agents (sodium
benzophenone ketyl, metal hydrides, Na/K alloy). Chloroform-d was
purchased from Cambridge Isototope Laboratories. Benzene-d6, toluene-
d8, o-xylene-d10, and cyclohexane-d12 (Cambridge Laboratories; all 99+
atom % D) used for NMR-scale reactions and thermolysis experiments
were stored in vacuo over Na/K alloy in resealable bulbs and were
vacuum-transferred immediately prior to use. All organic starting
materials were purchased from Aldrich Chemical Co., Farchan Labo-
ratories Inc., or Lancaster Synthesis Inc., and were used without further
purification unless otherwise stated. All substrates were vacuum-distilled
over CaH2, next dried twice over freshly activated Davison 4A
molecular sieves, and then were degassed by freeze-pump-thaw
methods. They were stored in vacuumtight storage flasks. Butadiene
was purified by passing through a MnO oxygen-removal column and
a Davison 4A molecular sieve column. The reagent 2-vinylnaphthalene
was vacuum-sublimed before use. The organolanthanide precatalysts
Cp′2LnCH(TMS)2 (Ln ) Sm, La; Cp′) η5-Me5C5)35 and Me2SiCp′′2-
LnCH(TMS)2 (Ln ) Sm, La; Cp′′ ) η5-Me4C5)36 were prepared by
published procedures. The reagents 4-(dimethylamino)styrene37 [2039-
80-7] and 4-(methylthio)styrene [18760-11-7] were synthesized from
the corresponding benzaldehydes by Wittig reactions according to
published procedures. The reagents 1,2-divinylbenzene [91-14-5], 2,3-
divinylnaphthalene38 [34299-60-0], 1,2,3-trivinylbenzene39 [114310-41-
7], and methylenecyclopropane40 [6142-73-0] were synthesized ac-
cording to published procedures. The reagent 2-phenylmethylene-
cyclopropane [29817-09-2] was purchased from Lancaster Synthesis
Inc. and was vacuum-distilled from CaH2.
lanthanide) raises the question of whether similar processes
could be used to effect intermolecular alkyne and alkene
hydroamination (e.g., eq 5). Indeed, limited examples of
organolanthanide-catalyzed intermolecular hydroamination have
been reported in a previous communication.25
Thermochemical data argue that the enthalpic constraints on
the intermolecular insertion and protonolysis steps in eq 5 should
be similar to those in the successful intramolecular processes
(eqs 3 and 4, overall ∆Hcalcd ≈ -13 and -35 kcal/mol,
repectively).26-29 However, it is likely that cyclohydroamination
benefits from substantial intramolecular entropic advantages30,31
over the corresponding intermolecular process (conceivably both
thermodynamic and kinetic),32,33 so that the feasibility, selectiv-
(23) For cyclohydroamination of amino-allenes, see: (a) Arredondo, V. M.;
McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949-1960. (b)
Arredondo, V. M.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1998,
120, 4871-4872.
(24) For cyclohydroamination of amino-dienes, see: (a) Hong, S.; Marks, T.
J. J. Am. Chem. Soc. 2002, 124, 7886-7887. (b) Hong, S.; Marks, T. J. J.
Am. Chem. Soc., in press.
(25) Li, Y.; Marks, T. J. Organometallics 1996, 15, 3770-3772.
(26) Requisite experimental thermochemical data are not available to compare
the thermodynamics of amine addition to olefins with that to alkynes.
However, ∆H for NH3 addition to ethylene can be estimated from
thermochemical data28,29 to be -13 kcal/mol. Calculations at the AM-1
level place NH3 addition to acetylene (to yield CH3CHdNH) as 17 kcal/
mol more exothermic than to ethylene. Furthermore, the addition of CH4
to acetylene is estimated from thermochemical data28,29 to be ∼14 kcal/
mol more exothermic than that to ethylene.
(27) 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.; Morss, L. R. J. Am. Chem. Soc. 1983, 105,
6824-6832.
(28) Organic fragment bond enthalpies from: (a) Griller, D.; Kanabus-Kaminska,
J. M.; Maccoll, A. J. Mol. Struct. 1988, 163, 125-131. (b) McMillan, D.
F.; Golden, D. M. Annu. ReV. Phys. Chem. 1982, 33, 493-532 and
references therein. (c) Benson, S. W. Thermochemical Kinetics, 2nd ed.;
Wiley: New York, 1976; Appendix Tables A.10, A.11, and A.22. (d)
Benson, S. W. J. Chem. Educ. 1965, 42, 502-518.
(29) Pedley, J. B.; Naylor, R. D.; Kirby, S. P. Thermochemical Data of Organic
Compounds, 2nd ed.; Chapman and Hall: London, 1986; Appendix Tables
1 and 3.
(30) For a discussion of the thermodynamic and kinetic advantages of intramo-
lecular reactions over intermolecular analogues, see: (a) Smith, G. M.;
Carpenter, J. D.; Marks, T. J. J. Am. Chem. Soc. 1986, 108, 6805-6807
and references therein. (b) Page, M. I. In The Chemistry of Enzyme Action;
Page, M. I., Ed.; Elsevier: New York, 1984; pp 1-54. (c) Kirby, A. J.
AdV. Phys. Org. Chem. 1980, 17, 183-278. (d) Page, M. I.; Jencks, W. P.
Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1678-1683.
Physical and Analytical Measurements. NMR spectra were
recorded on a Varian Gemini (FT; 300 MHz, 1H; 75 MHz, 13C),
Mercury-400 (FT; 400 MHz, 1H; 100 MHz, 13C), Unity-400 (FT; 400
(33) Steinborn, D.; Taube, R. Z. Chem. 1986, 26, 349. The ∆S° value for the
intermolecular NH insertion of NH3 into ethylene is ∼-30 cal/mol K. The
negative reaction entropy of the hydroamination of course drives the
equilibrium to the starting materials with increasing temperature.
(34) (a) He, M. Y.; Toscano, P. J.; Burwell, R. L.; Marks, T. J. J. Am. Chem.
Soc. 1985, 107, 641-652. (b) McIlwrick, C. R.; Phillips, C. S. G. J. Chem.
Phys., E 1973, 6, 1208-1210.
(35) Jeske, G.; Lauke, H.; Mauermann, H.; Swepston, P. N.; Schumann, H.;
Marks, T. J. J. Am. Chem. Soc. 1985, 107, 8091-8103.
(36) (a) Jeske, G.; Schock, L. E.; Mauermann, H.; Swepston, P. N.; Schumann,
H.; Marks, T. J. J. Am. Chem. Soc. 1985, 107, 8103-8110. (b) Stern, D.;
Sabat, M.; Marks, T. J. J. Am. Chem. Soc. 1990, 112, 9558-9575.
(37) Hollywood, F.; Suschitzky, H.; Hull, R. Synthesis 1982, 8, 662-665.
(38) Takeuchi, M.; Tuihiji, T.; Nishimura, J. J. Org. Chem. 1993, 58, 7388-
7392.
(31) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley: New York, 1992;
pp 210-214.
(32) For discussions of entropy and enthalpy effects on ring-closing reactions,
see: (a) Mandolini, L. Bull. Soc. Chim. Fr. 1988, 2, 173-176. (b) Detar,
D. F.; Luthra, N. P. J. Am. Chem. Soc. 1980, 102, 4505-4512. (c) For a
related discussion, see: Menger, F. M. Acc. Chem. Res. 1985, 18, 128-
134.
(39) Nakamura, Y.; Hayashida, Y.; Wada, Y.; Nishimura, J. Tetrahedron 1997,
53, 4593-4600.
(40) (a) Liptay, W. Angew. Chem., Int. Ed. Engl. 1969, 8, 177-188. (b) Salaun,
J. R.; Champion, J.; Conia, J. M. Org. Synth. 1977, 57, 36-40.
9
12586 J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003

Organolanthanide-Catalyzed Hydroamination
A R T I C L E S
MHz, 1H; 100 MHz, 13C), or Inova-500 (FT; 500 MHz, 1H; 125 MHz,
C6D6): 165.8, 164.9, 53.8, 53.4, 34.1, 34.1, 29.7, 25.1, 25.0, 19.3, 12.5,
12.4, -0.41, -0.92. 13C NMR (75 MHz, 1H-coupled, C6D6): δ 165.9
(s), 164.9 (s), 53.7 (t, JCH ) 129.0 Hz), 53.5 (t, JCH ) 129.7 Hz), 34.1
(t, JCH ) 119.1 Hz), 34.1 (t, JCH ) 119.1 Hz), 29.7 (q, JCH ) 125.0
Hz), 25.1 (t, JCH ) 116.6 Hz), 25.0 (t, JCH ) 128.9 Hz), 19.3 (q,
JCH ) 125.2 Hz), 12.5 (q, JCH ) 124.0 Hz), 12.4 (q, JCH ) 122.0 Hz),
-0.41 (q, JCH ) 118.7 Hz), -0.92 (q, JCH ) 118.7 Hz).
1
13C) instrument. Chemical 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). Elemental analyses were performed by Midwest
Microlabs, Indianapolis, IN. GCMS analyses were performed using an
HP6890 instrument with an HP-5MS (5% phenyl methyl siloxane, 30
m × 250 µm × 0.25 µm) capillary column and an FID detector. 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. HRMS studies were conducted on a VG
70-250 SE instrument with 70 eV electron impact ionization or chemical
ionization using CH4 as the reagent gas. IR spectra were recorded using
a Biorad FT S60 FTIR instrument.
The mixture of imine isomers described above in 0.6 mL of C7D8
was heated in a sealed NMR tube for 8 h at 120 °C to afford
N-(trimethylsilyl)-N-(1-methylethyl-1-enyl)propylamine (1), the rear-
rangement product, as a colorless liquid. The product was identified
by 1H, 13C, and 2D NMR and GC/MS. The yield (>90%) was
determined by 1H NMR and GC/MS after vacuum transfer of the
1
volatile products. H NMR (300 MHz, C7D8): δ 4.10 (d, J ) 3.9 Hz,
Typical NMR-Scale Catalytic Intermolecular Hydroamination
Reactions for Alkynes, Aliphatic Olefins, and Butadiene. In a
glovebox, the Me2SiCp′′2NdCH(SiMe3)2 precatalyst (2.0-35.0 mg,
3.3-58.0 µmol), olefin or alkyne (0.575-2.85 mmol, ∼35- to 333-
fold molar excess), and benzene (∼0.6 mL) were loaded into an NMR
tube equipped with a Teflon valve. On the high-vacuum line, the NMR
tube was evacuated and back-filled with argon three times. Then amine
(∼1.0-1.57 mmol, ∼10- to 52-fold molar excess; absolute concentra-
tions of amines were determined by internal FeCp2 calibration) was
vacuum-transferred in. The NMR tube was next back-filled with argon
and finally sealed. The reaction mixture was heated to 60 °C and
2H, CH2d), 2.90 (t, J ) 7.5 Hz, 2H, CH2N), 1.77 (s, 3H, dCCH3),
1.41 (m, 2H, CH2), 0.77 (t, J ) 7.5 Hz, 3H, CH3), 0.15 (s, 9H, Si-
(CH3)3). 13C NMR (75 MHz, C7D8): δ 148.5 (NCd), 93.2 (dCH2),
48.4 (NCH2), 23.5 (CH2), 22.7 (dCCH3), 11.6 (CH3), 1.79 (SiMe3).
MS (relative abundance): M+ (54), M+ - 1 (3), M+ + 1 (13), 156.1
(88), 142.1 (37), 128.1 (15), 114.1 (65), 98.1 (17), 73.1 (100), 59.0
(20), 45.0 (18). HRMS: calcd for C9H21NSi, 171.1443; found,
171.1431.
Synthesis of N-(Trimethylsilyl)-N-(1-methylethyl-1-enyl)butyl-
amine (2) [180140-31-2]. The title compound was synthesized in both
NMR- and preparative-scale reactions. Following the procedure above,
Me2SiCp′′2NdCH(SiMe3)2 precatalyst (2.0 mg, 3.3 µmol), 1-(trimeth-
ylsilyl)propyne (124 mg, 1.1 mmol, 333-fold molar excess), and
n-butylamine (2.3 mg, 31 µmol, 9.3-fold molar excess) in 0.6 mL of
C7D8 yielded the intermediate imine N-(1-methyl-2-(trimethylsilyl)-
ethylidene)butylamine, as a colorless liquid in the NMR-scale reaction.
1H NMR (300 MHz, C7D8): δ 3.10 (t, J ) 6.6 Hz, 2H, CH2N), 1.74
(s, 2H, CH2Si), 1.61 (m, 2H, CH2CH2N), 1.51 (s, 3H, CH3), 1.44 (m,
2H, CH2CH2CH2N), 0.92 (t, J ) 7.4 Hz, 3H, CH3). 13C NMR (75 MHz,
C7D8): δ 166, 51.3, 34.1, 33.9, 25.1, 21.1, 14.3, -0.99.
1
periodically monitored by H NMR spectroscopy. The final products
1
were identified by H, 13C, DEPT, and 2D NMR, GC/MS, and high-
resolution mass spectrometry.
Typical Preparative-Scale Catalytic Intermolecular Hydroami-
nation Reactions for Alkynes, Aliphatic Olefins, and Butadiene.
Scale-up catalytic reactions were carried out using the following
procedure. In the glovebox, 20.0 mg (33.2 µmol) of Me2SiCp′′2Nd-
CH(SiMe3)2, 1-(trimethylsilyl)propyne (295 mg, 2.63 mmol, 79-fold
excess), and C6H6 (5.0 mL) were loaded into a storage tube (25.0 mL)
equipped with a magnetic stir bar. Next, n-butylamine (183 mg, 2.5
mmol, 75-fold excess) was vacuum-transferred onto the precatalyst.
The mixture was then freeze-pump-thaw degassed and warmed to
room temperature. The resulting solution was stirred with heating to
60 °C for 3 days. Distillation of the C6H6 and excess 1-(trimethylsilyl)-
propyne at atmospheric pressure followed by vacuum transfer afforded
a mixture of N-(1-methyl-2-(trimethylsilyl)ethylidene)butylamine and
N-(trimethylsilyl)-N-(1-methylethyl-1-enyl)butylamine. After the mix-
ture was heated to 120 °C for 72 h, the N-(1-methyl-2-(trimethylsilyl)-
ethylidene)butylamine underwent isomerization to N-(trimethylsilyl)-
N-(1-methylethyl-1-enyl)butylamine. N-(Trimethylsilyl)-N-(1-methylethyl-
1-enyl)butylamine (2; 0.29 g, 62% isolated yield) was obtained as a
colorless oil. It was >95% pure by 1H and 13C NMR and GC/MS. See
the section below for characterization data.
The imine compound above in 0.6 mL of C7D8 was heated in a sealed
NMR tube for 8 h at 120 °C to afford N-(trimethylsilyl)-N-(1-
methylethyl-1-enyl)butylamine (2). The yield (>90%) was determined
by 1H NMR and GC/MS after vacuum transfer of the volatile products.
The scale-up catalytic reaction was carried out using the following
procedure. In the glovebox, 20.0 mg (33.2 µmol) of Me2SiCp′′2NdCH-
(SiMe3)2 was loaded into a storage tube (25 mL) equipped with a
magnetic stir bar. Next, C6H6 (5.0 mL), 1-(trimethylsilyl)propyne (295.2
mg, 2.63 mmol), and n-butylamine (182.9 mg, 2.5 mmol) were
successively vacuum-transferred onto the precatalyst. The mixture was
then freeze-pump-thaw degassed and warmed to room temperature.
The resulting solution was stirred with heating at 60 °C for 72 h.
Distillation of C6H6 and excess 1-(trimethylsilyl)propyne at atmospheric
pressure followed by vacuum transfer afforded a mixture of N-(1-
methyl-2-(trimethylsilyl)ethylidene)butylamine and the title compound
2. After the mixture was heated at 120 °C for 72 h, N-(1-methyl-2-
(trimethylsilyl)ethylidene)butylamine underwent isomerization to N-(tri-
methylsilyl)-N-(1-methylethyl-1-enyl)butylamine (2). N-(Trimethylsilyl)-
N-(1-methylethyl-1-enyl)butylamine (2; 0.29 g, 62% isolated yield) was
obtained as a colorless oil. 1H NMR (300 MHz, C6D6): δ 4.18 (s, 2H,
CH2Si), 2.98 (t, 2H, J ) 7.5 Hz, CH2N), 1.81 (s, 3H, CH3CdN), 1.45
(m, 2H, CH2CH2N), 1.20 (m, 2H, CH2CH3), 0.84 (t, J ) 7.2 Hz, 3H,
Synthesis of N-(Trimethylsilyl)-N-(1-methylethyl-1-enyl)propyl-
amine (1) [180140-30-1]. The title amine derivative was synthesized
catalytically using the procedure as described in typical NMR-scale
reactions. Me2SiCp′′2NdCH(SiMe3)2 precatalyst (2.0 mg, 3.3 µmol),
1-(trimethylsilyl)propyne (76 mg, 675 µmol, 205-fold molar excess),
and n-propylamine (9.3 mg, 160 µmol, 48-fold molar excess) in 0.6
mL of C7D8 afforded (E)- and (Z)-N-(1-methyl-2-(trimethylsilyl)-
ethylidene)propylamine (intermediate imine) as a colorless liquid in
the NMR-scale reaction. The intermediate imine concentrations were
determined by integration versus a ferrocene internal standard. 1H NMR
1
CH2CH3). 0.19 (s, 9H, Si(CH3)3). 13C NMR (75 MHz, H-decoupled,
C6D6): δ 148.9, 92.9, 46.6, 32.8, 23.1, 20.9, 14.4, 2.1. 13C NMR (75
1
1
(300 MHz, C6D6) of the major isomer (70% yield by H NMR): δ
MHz, H-coupled, C6D6): δ 148.9 (s), 92.7 (t, JCH ) 157.0 Hz), 46.6
3.05 (t, J ) 6.7 Hz, 2H, CH2N), 1.75 (s, 2H, CH2Si), 1.67 (m, 2H,
CH2), 1.49 (s, 3H, dCMe), 0.95 (t, J ) 7.4 Hz, 3H, CH3), -0.07 (s,
(t, JCH ) 132.5 Hz), 32.8 (t, JCH ) 123.5 Hz), 23.1 (q, JCH ) 120.0
Hz), 20.9 (t, JCH ) 121.5 Hz), 14.5 (q, JCH ) 123.5 Hz), 2.1 (q, JCH
)
1
9H, SiMe3). H NMR (300 MHz, C6D6) of the minor isomer (30%
106.6 Hz). MS (relative abundance): M+ (11), M+ - 1 (2), 170.2 (66),
156.3 (4), 142.1 (48), 128.1 (18), 114.1 (82), 100.1 (6), 73.0 (100),
59.1 (16), 45.0 (17). HRMS: calcd for C10H23NSi, 185.1600; found,
185.1602.
1
yield by H NMR): δ 3.02 (t, J ) 6.7 Hz, 2H, CH2N), 1.84 (s, 2H,
CH2Si), 1.70-1.61 (m, 2H, CH2), 1.66 (s, 3H, CH3), 0.98 (t, J ) 7.4
Hz, 3H, CH3), -0.06 (s, 9H, SiMe3). 13C NMR (75 MHz, 1H-coupled,
9
J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003 12587

A R T I C L E S
Ryu et al.
Synthesis of N-(Trimethylsilyl)-N-(1-methylethyl-1-enyl)isobu-
tylamine (3) [180140-32-3]. A procedure analogous to that for
N-(trimethylsilyl)-N-(1-methylethyl-1-enyl)butylamine (2) above was
used in the synthesis of the title compound with Me2SiCp′′2NdCH-
(SiMe3)2 (2.0 mg, 3.3 µmol), 1-(trimethylsilyl)propyne (76 mg, 680
µmol, 205-fold molar excess), and isobutylamine (9.0 mg, 120 µmol,
37-fold excess) in 0.6 mL of C6D6. The yield (>90%) was determined
by 1H NMR and GC/MS after vacuum transfer of the volatile products.
The intermediate imine was characterized by 1H NMR. 1H NMR (300
MHz, C7D8): δ 2.88 (d, J ) 6.0 Hz, 2H, CH2N), 1.94 (m, 1H, CH),
1.74 (s, 2H, CH2Si), 1.50 (s, 3H, dCCH3), 0.99 (d, J ) 6.7 Hz, 6H,
116.1 (43), 102.1 (35), 84.1 (21), 73.0 (100), 59.0 (21), 45.0 (13).
HRMS: calcd for C8H21NSi, 159.1443; found, 159.1432.
Synthesis of N-(trans-2-Butenyl)-N-n-propyl-1-amine (7) [180140-
34-5]. In a glovebox, the Me2SiCp′′2NdCH(SiMe3)2 precatalyst (35.0
mg, 58.0 µmol) was weighed into an NMR tube having a Teflon valve.
Next, 1.0 mL of C6D6, 1,3-butadiene (154 mg, 2.85 mmol, 49-fold molar
excess), and n-propylamine (93 mg, 1.57 mmol, 27-fold molar excess)
were vacuum-transferred into the tube on the high-vacuum line. Only
1
the trans-1,4-addition product was detected in the H NMR spectrum
(90% yield) by comparison with an authentic sample prepared from
1
the reaction of n-propylamine with trans-1-chloro-2-butene. H NMR
1
2CH3), 0.04 (s, 9H, SiMe3). 13C NMR (75 MHz, H-coupled, C7D8):
(300 MHz, C6D6): δ 5.65-5.45 (m, 2H, 2CHd), 3.04 (d, J ) 6.0 Hz,
2H, dCCH2N), 2.40 (t, J ) 7.5 Hz, 2H, CH2N), 1.58 (d, J ) 4.8 Hz,
3H, CH3Cd), 1.48 (m, 2H, CH2), 0.88 (t, J ) 7.8 Hz, 3H, CH3), 0.57
(br s, 1H, NH). 13C NMR (75 MHz, C6D6): δ 129.6, 126.7, 51.6, 51.2,
δ 165.9 (s, CdN), 59.7 (t, JCH ) 128.7 Hz, CH2N), 34.0 (t, JCH
)
119.1 Hz, CH2Si), 30.5 (d, JCH ) 126.2 Hz, CH), 29.6 (q, JCH ) 125.0
Hz, CH3), 21.1 (q, JCH ) 128.2 Hz, 2CH3), -0.92 (q, JCH ) 117.5 Hz,
SiMe3).
23.1, 17.5, 11.6. MS (relative abundance): M+ (7), M+ -1 (11), M+
+
1 (7), 98.2 (13), 84.1 (100), 66.1 (23), 55.1 (100), 43.1 (19). HRMS:
calcd for C7H15N, 113.1204; found, 113.1201.
The imine was heated at 120 °C for 8 h to afford the title compound
as a colorless liquid. H NMR (300 MHz, C7D8): δ 4.21 (d, J ) 5.1
1
Synthesis of N-n-Propyl-1-methyl-n-butyl-1-amine (8) [39190-
86-8]. An NMR tube with a Teflon valve was charged with Me2SiCp′′2-
NdCH(SiMe3)2 precatalyst (3.0 mg, 5.0 µmol) and a mixture of
1-pentene (125 mg, 1780 µmol, 365-fold molar excess) and n-
propylamine (1.5 mg, 25 µmol, 5-fold molar excess) in 0.6 mL of C6D6.
The reaction mixture was heated to 60 °C while being monitored by
1H NMR spectroscopy. Only the Markovnikov addition product was
Hz, 2H, CH2d), 2.72 (d, J ) 7.2 Hz, 2H, CH2N), 1.74 (s, 3H, dCCH3),
1.51 (m, 1H, CH), 0.80 (d, J ) 6.6 Hz, 6H, 2CH3), 0.15 (s, 9H, SiMe3).
13C NMR (75 MHz, C7D8): δ 148.7, 96.7, 53.8, 28.3, 2.0, 20.6, 1.63.
MS (relative abundance): M+ (33), M+ - 1 (2), M+ + 1 (9), 170.1
(52), 142.1 (70), 128.1 (15), 114.1 (40), 98.1 (9), 73.0 (100), 57.1 (22),
41.0 (21). HRMS: calcd for C10H23NSi, 185.1600; found, 185.1581.
Synthesis of N-(1-Methyl-2-phenylethylidene)propylamine (4)
[180140-33-4]. A procedure analogous to that for 1 above was used in
the synthesis of the title imine with Me2SiCp′′2NdCH(SiMe3)2 (3.0 mg,
5.0 µmol), 1-phenylpropyne (78 mg, 675 µmol, 135-fold molar excess),
and n-propylamine (15.5 mg, 260 µmol, 52-fold excess) in 0.6 mL of
C6D6. The yield (>85%) was determined by 1H NMR and GC/MS after
1
detected in the H NMR spectrum by comparison with an authentic
sample prepared from the reaction of n-propylamine with 2-bromopen-
1
tane. The yield (90%) was determined by H NMR and GC/MS after
1
vacuum transfer of the volatile products. H NMR (300 MHz, C6D6):
δ 2.54-2.36 (m, 3H), 1.42-1.33 (m, 2H), 1.31-1.17 (m, 4H), 0.95
(d, J ) 6.3 Hz, 3H), 0.87 (t, J ) 7.2 Hz, 6H), 0.61 (br s, 1H, NH). 13
C
1
vacuum transfer of the volatile products. H NMR (300 MHz, C7D8):
NMR (75 MHz, C6D6): δ 53.2, 49.5, 40.1, 24.2, 20.8, 19.5, 14.6, 12.1.
MS (relative abundance): M+ (3), M+ - 1 (3), M+ + 1 (1), 114.2
(15), 100.2 (12), 86.1 (100), 70.1 (5), 58.1 (8), 44.1 (36). HRMS: calcd
for C8H19N, 129.1517; found, 129.1514.
δ 7.16-7.09 (m, 5H, Ph), 3.44 (s, 2H, CH2Ph), 3.03 (t, J ) 6.8 Hz,
2H, CH2N), 1.70 (m, 2H, CH2), 1.32 (s, 3H, dCCH3) 0.95 (t, J )
7.4 Hz, 3H, CH3). 13C NMR (75 MHz, C6D6): δ 166.6, 129.4, 128.7,
126.6, 123.4, 53.4, 49.8, 24.6, 16.1, 12.4. MS (relative abundance):
M+ (4), 146.2 (5), 115.2 (5), 105.2 (5), 91.1 (23), 84.2 (65), 65.1 (8),
42.1 (100). HRMS: calcd for C12H17N, 175.1361; found, 175.1359.
Typical NMR-Scale Catalytic Intermolecular Hydroamination
Reactions for Vinylarenes and Di- and Trivinylarenes. In a nitrogen-
filled glovebox, the (η5-Me5C5)2LaCH(SiMe3)2 precatalyst (7.2 mg, 12.6
µmol) was weighed into an NMR tube equipped with a Teflon valve,
and C7D8 (0.4 mL), n-propylamine (7.4 mg, 126 µmol), and vinylarene
(1.26 mmol) were added in turn. The tube was then removed from the
glovebox. The catalyst:amine:vinylarene ratio was confirmed as 1:10:
Synthesis of N-(2-Butylidene)propylamine (5) [3332-11-4]. A
procedure analogous to that for 1 above was used in the synthesis of
the title compound with Me2SiCp′′2NdCH(SiMe3)2 (3.0 mg, 5.0 µmol),
2-butyne (37 mg, 680 µmol, 135-fold molar excess), and n-propylamine
(9.3 mg, 160 µmol, 32-fold molar excess) in 0.6 mL of C6D6. The
1
100 by H NMR, on the basis of the quantitatively generated internal
1
yield (91%) was determined by H NMR and GC/MS after vacuum
CH2(SiMe3)2 standard. The tube was then brought to the indicated
1
transfer of the volatile products. H NMR (300 MHz, C6D6): δ 3.09
reaction temperature (90 °C) and the ensuing catalytic reaction
(t, J ) 6.4 Hz, 2H, CH2N), 2.09 (q, J ) 7.4 Hz, 2H, MeCH2CdN),
1.75 (m, 2H, CH2), 1.36 (s, 3H, CH3CdN), 1.09 (t, J ) 7.4 Hz, 3H,
CH3CH2Cd), 1.00 (t, J ) 7.4 Hz, 3H, CH3). 13C NMR (100 MHz,
C6D6): δ 167.9, 53.2, 35.3, 24.7, 12.4, 10.7, 1.4. MS (relative
abundance): M+ (23), M+ + 1 (2), M+ - 1 (2), 98.1 (7), 84.1 (100),
56.1 (40), 42.1 (65). HRMS: calcd for C7H15N: 113.1204; found,
113.1186.
1
monitored by H NMR. After the reaction was complete, Et2O (1.0
mL) was added to the reaction mixture. The instantaneously precipitated
polystyrene and catalyst were filtered off through a pad of Al2O3, and
the pad was washed with Et2O (1.0 mL). The solvent was carefully
removed on the rotary evaporator, and then the residue was diluted
with anhydrous Et2O (1 mL). A 2.0 M solution of Et2O‚HCl (0.15 mL,
0.3 mmol) was next added dropwise with stirring at 0 °C. After the
mixture was stirred at 0 °C for 30 min, the solvent was removed in
vacuo. The final product was purified by recrystallization from hot
benzene-pentane.
Preparative-Scale Catalytic Intermolecular Hydroamination
Reactions. Synthesis of N-Propylphenethylamine (9) [27906-91-8].
In a glovebox, (η5-Me5C5)2LaCH(TMS)2 precatalyst (28.5 mg, 50
µmol), n-propylamine (59.1 mg, 1.0 mmol), styrene (208 mg, 2.0
mmol), and C6D6 (1.0 mL) were loaded into a storage tube equipped
with a magnetic stir bar and J. Young valve. The valve was then closed
and the clear solution stirred for 40 h at 90 °C behind a blast shield.
Et2O (2.0 mL) was next added to the reaction mixture. The instanta-
neously precipitated polystyrene and catalyst were filtered off through
a pad of Al2O3, which was then washed with Et2O (2.0 mL). The solvent
was removed in vacuo. Column chromatography on silica gel (meth-
Synthesis of N-(2-(Trimethylsilyl)ethyl)-N-n-propyl-1-amine (6)
[41269-62-9]. An NMR tube with a Teflon valve was charged with
Me2SiCp′′2SmCH(SiMe3)2 precatalyst (10.0 mg, 16.4 µmol) and a
mixture of 1-(trimethylsilyl)ethylene (58 mg, 570 µmol, 35-fold molar
excess) and n-propylamine (9.6 mg, 160 µmol, 10-fold molar excess)
in 0.6 mL of C6D6. The reaction mixture was heated to 60 °C while
1
being monitored by H NMR spectroscopy. Only the title compound
was detected in 93% yield. The yield was determined by 1H NMR and
1
GC/MS after vacuum transfer of the volatile products. H NMR (300
MHz, C6D6): δ 2.57 (m, 2H, CH2N), 2.45 (m, 2H, CH2N), 1.41 (m,
2H, CH2CH3), 0.89 (t, J ) 7.4 Hz, 3H, CH3), 0.68 (t, J ) 8.0 Hz, 2H,
CH2SiMe3), 0.31 (br s, 1H, NH), 0.03 (s, 9H, Si(CH3)3). 13C NMR (75
MHz, C6D6): δ 52.1, 46.1, 23.8, 18.5, 12.2, 1.2. MS (relative
abundance): M+ (14), M+ + 1 (3), M+ - 1 (3), 145.1 (4), 130.1 (39),
9
12588 J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003

Organolanthanide-Catalyzed Hydroamination
A R T I C L E S
ylene chloride-hexane-isopropylamine, 1:15:0.8) afforded pure amine
9 (146 mg; 90% yield) as a colorless liquid, Rf ) 0.43. 1H NMR (400
MHz, C6D6): δ 7.19-7.06 (m, 5H), 2.72 (t, J ) 6.4 Hz, 2H), 2.65
(2H, J ) 6.4 Hz, 2H), 240 (t, J ) 7.2 Hz, 2H), 1.34 (sextet, J )
7.2 Hz, 2H), 0.83 (t, J ) 7.2 Hz, 3H), 0.63 (br s, 1H). 13C NMR (100
MHz, C6D6): δ 141.326, 129.444, 129.004, 126.631, 52.565, 52.209,
37.681, 24.290, 12.666. MS (relative abundance): M+ + 1 (15), M+
(100), 154.0 (20), 145.1 (4), 124.1 (5), 122.0 (5), 97.1 (5), 95.1 (7),
91.1 (15), 85.1 (32), 81.1 (35), 79.1 (37), 71.1 (56), 69.1 (72), 67.1
(50); HRMS: calcd for C11H18N, 164.1434; found, 164.1433.
off through a pad of Al2O3, and the pad was washed with MeOH (2.0
mL). The solvent was then removed in vacuo. Column chromatography
on silica gel (methylene chloride-hexane-isopropylamine, 1:15:0.8)
afforded the pure amine 12 (159 mg; 88% yield), Rf ) 0.41. 1H NMR
(500 MHz, C6D6): δ 6.86-6.79 (m, 4H), 2.60 (t, J ) 7.0 Hz, 2H),
2.50 (t, J ) 7.0 Hz, 2H), 2.38 (t, J ) 7.0 Hz, 2H), 1.34 (sextet, J )
7.0 Hz, 2H), 0.84 (t, J ) 7.0 Hz, 3H). 13C NMR (125 MHz, C6D6): δ
162.3 (d, JCF ) 242 Hz), 136.9, 130.8 (d, JCF ) 7.75 Hz), 115.6 (d,
JCF ) 20.9 Hz), 52.3, 51.9, 36.5, 24.0, 19.3.
The amine 12 (159 mg, 0.88 mmol) was diluted with anhydrous
Et2O (2.0 mL). A 2.0 M ether solution of HCl (1.0 mL, 2.0 mmol)
was added dropwise with stirring at 0 °C. After the mixture was stirred
at 0 °C for 30 min, the solvent was removed in vacuo. Washing the
resulting solid with Et2O (2 × 2.0 mL) afforded the analytically pure
HCl salt of amine 12 as a white crystalline solid (174 mg; 91% yield).
1H NMR (500 MHz, CDCl3): δ 7.19 (dd, JHH ) 8.5 Hz, JHF ) 5.0 Hz,
2H), 6.96 (dd, JHH ) 8.5 Hz, JHF ) 8.5 Hz, 2H), 3.26 (m, 2H), 3.14
(m, 2H), 2.93 (m, 2H), 1.94 (sextet, J ) 7.5 Hz, 2H), 1.00 (t, J ) 7.5
Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 162.1 (d, JCF ) 244 Hz)
Synthesis of Propyl(2-(p-tolyl)ethyl)amine (10) [181495-51-2]
Hydrochloride. In a glovebox, (η5-Me5C5)2LaCH(TMS)2 precatalyst
(28.5 mg, 50 µmol), n-propylamine (59.1 mg, 1.0 mmol), 4-methyl-
styrene (236 mg, 2.0 mmol), and C6D6 (1 mL) were loaded into a
storage tube equipped with a magnetic stir bar and J. Young valve.
The valve was then closed and the clear solution stirred for 68 h at 90
°C behind a blast shield. Et2O (2.0 mL) was next added to the reaction
mixture. The instantaneously precipitated polystyrene and catalyst were
filtered off through a pad of Al2O3, and the pad was washed with Et2O
(2.0 mL). The solvent was carefully removed on the rotary evaporator,
and then the residue was diluted with anhydrous Et2O (2.0 mL). A 2.0
M ether solution of HCl (1.0 mL, 2.0 mmol) was added dropwise with
stirring at 0 °C. After the mixture was stirred at 0 °C for 30 min, the
solvent was removed in vacuo. Washing the resulting solid with Et2O
(2 × 2.0 mL) afforded the analytically pure HCl salt of amine 10 as a
white crystalline solid (198 mg; 93% yield). 1H NMR (500 MHz,
CDCl3): δ 9.72 (br s, 2H), 7.12-7.08 (m, 4H), 3.22 (m, 2H), 3.15 (m,
2H), 2.93 (m, 2H), 2.30 (s, 3H), 1.96 (m, 2H), 1.00 (t, J ) 7.0 Hz,
3H). 13C NMR (125 MHz, CDCl3): δ 136.8, 133.6, 129.6, 128.7, 49.7,
49.4, 32.0, 21.2, 19.7, 11.5. MS (relative abundance): M+ - Cl (2),
162.2 (10), 148.0 (6), 119.2 (19), 105.2 (11), 91.1 (10), 72.1 (100),
44.9 (12), 34.4 (26). HRMS: calcd for C12H19N+, 177.15175; found,
177.15268. Anal. Calcd for C12H20NCl: C, 67.43; H, 9.43; N, 6.55.
Found: C, 67.28; H, 9.36; N, 6.52.
132.4 (d, JCF ) 2.88 Hz), 130.3 (d, JCF ) 7.75 Hz), 115.9 (d, JCF
)
21.3 Hz), 49.8, 49.3, 31.6, 19.3, 11.5. Anal. Calcd for C11H17NClF:
C, 60.69; H, 7.87; N, 6.43. Found: C, 60.37; H, 7.79; N, 6.32.
Synthesis of N-Propyl-4-(trifluoromethyl)phenethylamine (13)
Hydrochloride. In a glovebox, (η5-Me5C5)2LaCH(TMS)2 precatalyst
(28.5 mg, 50 µmol), n-propylamine (59.1 mg, 1.0 mmol), 4-(trifluo-
romethyl)styrene (344 mg, 2.0 mmol), and C6D6 (1 mL) were loaded
into a storage tube equipped with a magnetic stir bar and J. Young
valve. The valve was next closed and the clear solution stirred for 34
h at 90 °C behind a blast shield. MeOH (2.0 mL) was then added to
the reaction mixture. The instantaneously precipitated polymer and
catalyst were filtered off through a pad of Al2O3, and the pad was
washed with MeOH (2.0 mL). The solvent was then removed in vacuo.
Column chromatography on silica gel (methylene chloride-hexane-
isopropylamine, 1:15:0.8) afforded the pure amine 13 (192.0 mg; 83%
1
yield): Rf ) 0.40. Data for free amine 13 are as follows. H NMR
Synthesis of (2-(Naphthalen-2-yl)ethyl)propylamine (11) [181495-
57-8] Hydrochloride. In a glovebox, (η5-Me5C5)2LaCH(TMS)2 pre-
catalyst (28.5 mg, 50 µmol), n-propylamine (59.1 mg, 1.0 mmol),
2-vinylnaphthalene (308 mg, 2.0 mmol), and C6D6 (1 mL) were loaded
into a storage tube equipped with a magnetic stir bar and J. Young
valve. The valve was next closed and the clear solution stirred for 72
h at 90 °C behind a blast shield. Et2O (2.0 mL) was next added to the
reaction mixture. The instantaneously precipitated polyvinylnaphthalene
and catalyst were filtered off through a pad of Al2O3, and the pad was
then washed with Et2O (2.0 mL). The solvent was carefully removed
on the rotary evaporator, and then the residue was diluted with
anhydrous Et2O (2.0 mL). A 2.0 M ether solution of HCl (1.0 mL, 2.0
mmol) was added dropwise with stirring at 0 °C. After the mixture
was stirred at 0 °C for 30 min, the solvent was removed in vacuo.
Washing the resulting solid with Et2O (2 × 2.0 mL) afforded the
analytically pure HCl salt of amine 11 as a white crystalline solid (229
mg; 92% yield). 1H NMR (500 MHz, CDCl3): δ 9.87 (br s, 2H), 7.78-
7.70 (m, 2H), 7.74 (d, J ) 8.5 Hz, 1H), 7.68 (s, 1H), 7.44-7.42 (m,
2H), 7.35 (d, J ) 8.5 Hz, 1H), 3.50 (t, J ) 8.0 Hz, 2H), 3.29 (m, 2H),
2.99 (m, 2H), 2.01 (sextet, J ) 7.5 Hz, 2H), 1.02 (t, J ) 7.5 Hz, 3H).
13C NMR (125 MHz, CDCl3): δ 134.1, 133.6, 132.5, 128.8, 127.8,
127.7, 127.4, 126.9, 126.4, 126.0, 49.8, 49.2, 32.6, 19.8, 11.5. Anal.
Calcd for C15H20NCl: C, 72.13; H, 8.07; N, 5.61. Found: C, 72.04;
H, 8.12; N, 5.56.
(400 MHz, CDCl3): δ 7.55 (d, J ) 8.0 Hz, 2H), 7.32 (d, J ) 8.0 Hz,
2H), 2.91-2.85 (m, 4H), 2.60 (t, J ) 7.2 Hz, 2H), 1.49 (sextet, J )
7.2 Hz, 2H), 0.90 (t, J ) 7.2 Hz, 3H).
The amine 13 (192 mg, 0.83 mmol) was diluted with anhydrous
Et2O (2.0 mL). A 2.0 M ether solution of HCl (1.0 mL, 2.0 mmol)
was added dropwise with stirring at 0 °C. After the mixture was stirred
at 0 °C for 30 min, the solvent was removed in vacuo. Washing the
resulting solid with Et2O (2 × 2.0 mL) afforded the analytically pure
HCl salt of amine 13 as a white crystalline solid (187 mg; 84% yield).
1H NMR (500 MHz, CDCl3): δ 9.86 (br s, 2H), 7.55 (d, J ) 8.0 Hz,
2H), 7.36 (d, J ) 8.0 Hz, 2H), 3.38 (m, 2H), 3.18 (m, 2H), 2.96 (m,
2H), 1.95 (sextet, J ) 7.5 Hz, 2H), 1.02 (t, J ) 7.5 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 140.7, 129.8 (q, JCF ) 32.4 Hz), 129.2, 126.0
(q, JCF ) 3.9 Hz), 125.2 (q, JCF ) 270 Hz), 49.8, 48.9, 32.2, 19.8,
11.5. Anal. Calcd for C12H17NClF3: C, 53.84; H, 6.40; N, 5.23.
Found: C, 53.98; H, 6.42; N, 5.21.
Synthesis of 4-Methoxy-N-propylphenethylamine (14) Hydro-
chloride [101566-01-2]. In a glovebox, (η5-Me5C5)2LaCH(TMS)2
precatalyst (28.5 mg, 50 µmol), n-propylamine (59.1 mg, 1.0 mmol),
4-methoxystyrene (268 mg, 2.0 mmol), and C6D6 (1 mL) were loaded
into a storage tube equipped with a magnetic stir bar and J. Young
valve. The valve was then closed and the clear solution stirred for 7
days at 90 °C behind a blast shield. Et2O (2.0 mL) was next added to
the reaction mixture. The instantaneously precipitated polymer and
catalyst were filtered off through a pad of Al2O3, and the pad was
washed with Et2O (2.0 mL). The solvent was carefully removed on
the rotary evaporator, and then the residue was diluted with anhydrous
Et2O (2.0 mL). A 2.0 M ether solution of HCl (1.0 mL, 2.0 mmol)
was added dropwise with stirring at 0 °C. After the mixture was stirred
at 0 °C for 30 min, the solvent was removed in vacuo. Washing the
resulting solid with Et2O (2 × 2.0 mL) afforded the analytically pure
Synthesis of 4-Fluoro-N-propylphenethylamine (12) Hydrochlo-
ride. In a glovebox, (η5-Me5C5)2LaCH(TMS)2 precatalyst (28.5 mg,
50 µmol), n-propylamine (59.1 mg, 1.0 mmol), 4-fluorostyrene (244
mg, 2.0 mmol), and C6D6 (1 mL) were loaded into a storage tube
equipped with a magnetic stir bar and J. Young valve. The valve was
next closed and the clear solution stirred for 6 days at 100 °C behind
a blast shield. MeOH (2.0 mL) was then added to the reaction mixture.
The instantaneously precipitated polystyrene and catalyst were filtered
9
J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003 12589

A R T I C L E S
Ryu et al.
HCl salt of amine 14 as a white crystalline solid (188 mg; 82% yield).
1H NMR (500 MHz, CDCl3): δ 9.73 (br s, 2H) 7.15 (d, J ) 8.5 Hz,
2H), 6.82 (d, J ) 8.5 Hz, 2H), 3.77 (s, 3H), 3.23 (m, 2H), 3.16 (m,
2H), 2.93 (quintet, J ) 7.5 Hz, 2H), 1.96 (sextet, J ) 7.5 Hz, 2H),
1.01 (t, J ) 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 158.8, 129.9,
128.7, 114.4, 55.4, 49.7, 49.5, 31.6, 19.7, 11.5. Anal. Calcd for C12H20-
NOCl: C, 62.73; H, 8.77; N, 6.10. Found: C, 61.68; H, 8.80; N, 6.03.
Synthesis of 4-(Dimethylamino)-N-propylphenethylamine (15).
In a glovebox, (η5-Me5C5)2LaCH(TMS)2 precatalyst (28.5 mg, 50
µmol), n-propylamine (59.1 mg, 1.0 mmol), 4-(dimethylamino)styrene
(294 mg, 2.0 mmol), and C6D6 (1 mL) were loaded into a storage tube
equipped with a magnetic stir bar and J. Young valve. The valve was
then closed and the clear solution stirred for 10 days at 90 °C behind
a blast shield. MeOH (2.0 mL) was next added to the reaction mixture.
The instantaneously precipitated polymer and catalyst were filtered off
through a pad of Al2O3, and the pad was washed with MeOH (2.0
mL). The solvent was then removed in vacuo. Column chromatography
on silica gel (methylene chloride-hexane-isopropylamine, 1:15:0.8)
silica gel (EtOAc-hexane, 1:1) afforded pure amine 18 (155 mg; 82%
yield), Rf ) 0.22. 1H NMR (500 MHz, CDCl3): δ 7.14-7.09 (m, 4H),
3.90 (q, J ) 6.5 Hz, 1H), 3.09 (m, 1H), 2.94 (m, 1H), 2.79 (m, 1H),
2.72 (dt, J ) 16 Hz, J ) 4.0 Hz, 1H), 2.56 (m, 2H), 1.62 (m, 2H),
1.36 (d, J ) 6.5 Hz, 3H), 0.95 (t, J ) 8.0 Hz, 3H). 13C NMR (125
MHz, CDCl3): δ 140.5, 134.4, 129.0, 127.6, 125.9, 125.8, 56.6, 56.1,
44.1, 27.4, 21.0, 19.4, 12.2. Anal. Calcd for C13H19N: C, 82.48; H,
10.12; N, 7.40. Found: C, 82.41; H, 10.16; N, 7.40.
Synthesis of 1-Methyl-2-propyl-1,2,3,4-tetrahydrobenzo[g]iso-
quinoline (20). In a glovebox, (η5-Me5C5)2LaCH(TMS)2 precatalyst
(28.5 mg, 50 µmol), n-propylamine (59.1 mg, 1.0 mmol), 2,3-
divinylnaphthalene (360 mg, 2.0 mmol), and C6D6 (1 mL) were loaded
into a storage tube equipped with a magnetic stir bar and J. Young
valve. The valve was then closed and the clear solution stirred for 22
h at 90 °C behind a blast shield. MeOH (2.0 mL) was next added to
the reaction mixture. The instantaneously precipitated polymer and
catalyst were filtered off through a pad of Al2O3, and the pad was
washed with MeOH (2.0 mL). The solvent was removed in vacuo.
Column chromatography on silica gel (EtOAc-hexane, 1:1) afforded
1
afforded pure amine 15 (62.0 mg; 30% yield), Rf ) 0.48. H NMR
1
pure amine 20 (220 mg; 92% yield), Rf ) 0.32. H NMR (500 MHz,
(500 MHz, CDCl3): δ 7.00 (d, J ) 8.5 Hz, 2H), 6.80 (d, J ) 8.5 Hz,
2H), 2.93 (s, 6H), 2.84 (t, J ) 7.5 Hz, 2H), 2.73 (t, J ) 7.0 Hz, 2H),
2.58 (t, J ) 7.0 Hz, 2H), 1.49 (sextet, J ) 7.5 Hz, 2H), 0.90 (t, J )
7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 149.4, 129.5, 128.4,
113.2, 52.0, 51.7, 41.1, 35.5, 23.4, 12.0. Anal. Calcd for C13H22N2: C,
75.68; H, 10.75; N, 13.58. Found: C, 75.64; H, 10.79; N, 12.29.
Synthesis of 4-(Methylthio)-N-propylphenethylamine (16) Hy-
drochloride. In a glovebox, (η5-Me5C5)2LaCH(TMS)2 precatalyst (28.5
mg, 50 µmol), n-propylamine (59.1 mg, 1.0 mmol), 4-(methylthio)-
styrene (300 mg, 2.0 mmol), and C6D6 (1 mL) were loaded into a
storage tube equipped with a magnetic stir bar and J. Young valve.
The valve was then closed and the clear solution stirred for 34 h at
90 °C behind a blast shield. MeOH (2.0 mL) was next added to the
reaction mixture. The instantaneously precipitated polymer and catalyst
were filtered off through a pad of Al2O3, and the pad was washed with
MeOH (2.0 mL). The solvent was removed in vacuo. Column
chromatography on silica gel (methylene chloride-hexane-isopropy-
lamine, 1:15:0.8) afforded pure amine 16 (178 mg; 85% yield), Rf )
0.40. Data for the free amine are as follows. 1H NMR (400 MHz,
CDCl3): δ 7.20 (d, J ) 8.8 Hz, 2H), 7.13 (d, J ) 8.8 Hz, 2H), 2.84 (t,
J ) 6.8 Hz, 2H), 2.76 (t, J ) 6.8 Hz, 2H), 2.57 (t, J ) 7.2 Hz, 2H),
2.46 (s, 3H), 1.48 (sextet, J ) 7.2 Hz, 2H), 0.88 (t, J ) 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 137.4, 129.4, 127.2, 126.7, 52.0, 51.4,
36.1, 23.4, 16.5, 12.0.
C6D6): δ 7.66 (t, J ) 9.0 Hz, 2H), 7.40 (s, 1H), 7.37 (s, 1H), 7.30-
7.28 (m, 2H), 3.95 (q. J ) 6.5 Hz, 1H), 3.00-2.89 (m, 2H), 2.72 (dt,
J ) 17.0 Hz, 5.0 Hz, 1H), 2.58 (dt, J ) 12.0 Hz, 5.0 Hz, 1H), 2.50-
2.41 (m, 2H), 1.52 (sextet, J ) 7.5 Hz, 2H), 1.33 (d, J ) 6.5 Hz, 3H),
0.94 (t, J ) 7.5 Hz, 3H). 13C NMR (125 MHz, C6D6): δ 140.4, 134.2,
133.1, 133.1, 128.1, 127.7, 127.5, 126.3, 125.8, 125.6, 57.8, 56.5, 45.0,
28.7, 21.8, 20.7, 12.5. HRMS (m/z): calcd for C17H21N (M+), 239.1674;
found, 239.1669. Anal. Calcd for C17H21N: C, 85.30; H, 8.84; N, 5.85.
Found: C, 85.61; H, 8.96; N, 5.60.
Synthesis of (()-(1R,2aR)-1-Methyl-3-propyl-1,2,2a,3,4,5-hexahy-
dro-3-azaacenaphthylene (22). In a glovebox, (η5-Me5C5)2LaCH-
(TMS)2 precatalyst (28.5 mg, 50 µmol), n-propylamine (59.1 mg, 1.0
mmol), 1,2,3-trivinylbenzene (312.0 mg, 2.0 mmol), and C6D6 (1 mL)
were loaded into a storage tube equipped with a magnetic stir bar and
J. Young valve. The valve was then closed and the clear solution stirred
for 24 h at 90 °C behind a blast shield. MeOH (2.0 mL) was next
added to the reaction mixture. The instantaneously precipitated polymer
and catalyst were filtered off through a pad of Al2O3, and the pad was
washed with MeOH (2.0 mL). The solvent was removed in vacuo.
Column chromatography on silica gel (EtOAc-hexane, 1:1) afforded
1
pure amine 22 (189 mg; 88% yield), Rf ) 0.40. H NMR (500 MHz,
C6D6): δ 7.13 (dd, J ) 7.5 Hz, J ) 7.0 Hz, 1H, H7), 6.94 (d, J ) 7.0
Hz, 1H), 6.87 (d, J ) 7.5 Hz, 1H), 3.21 (dd, J ) 8.5 Hz, J ) 6.0 Hz,
1H), 3.01-2.95 (m, 2H), 2.84 (m, 1H) 2.61-2.53 (m, 2H), 2.26
(quintet, J ) 5.5 Hz, 1H), 2.14 (td, J ) 12.5 Hz, J ) 5.5 Hz, 1H),
2.04 (m, 1H), 1.46 (m, 2H), 1.36 (dd, J ) 11.0 Hz, J ) 10.5 Hz, 1H),
1.12 (d, J ) 6.5 Hz, 3H), 0.91 (t, J ) 7.5 Hz, 3H). 13C NMR (125
MHz, C6D6): δ 146.7, 143.4, 132.5, 127.9, 125.4, 120.5, 66.9, 57.9,
51.8, 45.1, 37.8, 28.7, 21.1, 18.9, 12.7. Anal. Calcd for C15H21N: C,
83.67; H, 9.83; N, 6.50. Found: C, 83.51; H, 9.77; N, 6.69.
The amine 16 (178 mg, 0.85 mmol) was diluted with anhydrous
Et2O (2.0 mL). A 2.0 M ether solution of HCl (1.0 mL, 2.0 mmol)
was added dropwise with stirring at 0 °C. After the mixture was stirred
at 0 °C for 30 min, the solvent was removed in vacuo. Washing the
resulting solid with Et2O (2 × 2.0 mL) afforded the analytically pure
HCl salt of amine 16 as a white crystalline solid (160 mg; 77% yield).
1H NMR (500 MHz, CDCl3): δ 9.77 (br s, 2H), 7.18 (AB doublet,
J ) 8.0 Hz, 2H), 7.15 (AB doublet, J ) 8.0 Hz, 2H), 3.26 (m, 2H),
3.15 (m, 2H), 2.94 (t, J ) 7.0 Hz, 2H), 2.46 (s, 3H), 1.96 (sextet, J )
7.5 Hz, 2H), 1.02 (t, J ) 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3):
δ 137.5, 133.4, 129.3, 127.2, 49.8, 49.3, 31.9, 19.8, 16.1, 11.5. Anal.
Calcd for C12H20NClS: C, 58.63; H, 8.20; N, 5.70; S, 13.04. Found:
C, 58.52; H, 8.10; N, 5.75; S, 13.02.
1
All H NMR resonances were assigned by COSY, and the relative
stereochemistry of H(2a) and Me(1) was confirmed by a NOESY
experiment. H(2a) shows an NOE correlation with Heq(2), which is cis
to H(2a) at δ 3.12 ppm. Heq(2) at δ 2.26 ppm exhibited an NOE
correlation with Me(1) at δ 1.12 ppm and was confirmed as cis to
Me(1).
Synthesis of 1-Methyl-N-propyl-1,2,3,4-tetrahydroisoquinoline
(18). In a glovebox, (η5-Me5C5)2LaCH(TMS)2 precatalyst (28.5 mg,
50 µmol), n-propylamine (59.1 mg, 1.0 mmol), 1,2-divinylbenzene (260
mg, 2.0 mmol), and C6D6 (1 mL) were loaded into a storage tube
equipped with a magnetic stir bar and J. Young valve. The valve was
then closed and the clear solution stirred for 22 h at 90 °C behind a
blast shield. MeOH (2.0 mL) was next added to the reaction mixture.
The instantaneously precipitated polymer and catalyst were filtered off
through a pad of Al2O3, and the pad was washed with MeOH (2.0
mL). The solvent was removed in vacuo. Column chromatography on
Synthesis of N-(1-Methylpropylidene)-1-propanamine (28a) [3332-
11-4]. In a nitrogen-filled glovebox, the (η5-Me5C5)2LaCH(TMS)2
9
12590 J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003

Organolanthanide-Catalyzed Hydroamination
A R T I C L E S
precatalyst (28.5 mg, 15.8 µmol) was weighed into an NMR tube
equipped with a Teflon valve, and C6D6 (1.0 mL) was added. The tube
was then removed from the glovebox. On the high-vacuum line, the
NMR tube was evacuated and back-filled with argon three times. Then
n-propylamine (59 mg, 1.0 mmol) and methylenecyclopropane (54 mg,
1.0 mmol) were vacuum-transferred in. The NMR tube was next back-
filled with argon and finally sealed. The catalyst to substrate ratio was
7.0 Hz, 1H), 0.86 (d, J ) 6.5 Hz, 3H). 13C NMR (125 MHz, C6D6):
δ 147.4, 141.7, 129.0, 128.1, 128.0, 125.5, 116.7, 112.9, 47.1, 38.3,
32.1, 20.1. HRMS (m/z): calcd for C16H19N (M)+, 225.1512; found,
225.1509. LRMS (relative abundance): [M+ + 1] (40), [M+] (87), 210.1
(60), 132.1 (12), 121.1 (63), 120.1 (100), 93.1 (33), 91.1 (70), 77.0
(35), 65.0 (13).
Data for the minor products, a diastereomeric mixture of syn-34b
[91859-40-4] and anti-34b [91859-39-1], are as follows. 1H NMR (500
MHz, C6D6): δ 7.18-7.11 (m, 12H), 7.05 (d, J ) 7.0 Hz, 2H), 6.99
(d, J ) 7.0 Hz, 2H), 6.75-6.69 (m, 2H), 6.44 (t, J ) 7.5 Hz, 2H),
3.41 (dq, J ) 16.5 Hz, J ) 6.5 Hz, 1H), 3.07 (d, J ) 8.5 Hz, 1H), 2.96
(d, J ) 9.5 Hz, 1H), 2.78 (m, 1H), 2.69 (m, 1H), 1.11 (d, J ) 7.0 Hz,
3H), 1.05 (d, J ) 7.0 Hz, 3H), 0.82 (d, J ) 6.5 Hz, 3H), 0.72 (d, J )
6.5 Hz, 3H). 13C NMR (500 MHz, C6D6): δ 148.5, 144.6, 144.1, 130.1,
129.9, 129.0, 128.9, 128.8, 127.0, 126.9, 117.8, 117.7, 117.5, 114.1,
114.0, 113.9, 53.7, 51.9, 44.6, 44.2, 18.7, 17.8, 17.7, 16.2.
1
confirmed as 1:20.1 by H NMR, on the basis of the quantitatively
generated internal CH2(TMS)2 standard. The reaction mixture was
heated to 60 °C and periodically monitored by H NMR spectroscopy.
After 24 h, the reaction had proceeded to >95% conversion, as
1
determined by H NMR and GC-MS on the basis of the CH2(TMS)2
1
internal standard. H NMR (500 MHz, C6D6): δ 3.08 (t, J ) 7.5 Hz,
2H), 2.09 (q, J ) 7.5 Hz, 2H), 1.71 (sextet, J ) 7.5 Hz, 2H), 1.42 (s,
3H), 1.06 (t, J ) 7.5 Hz, 3H), 0.98 (t, J ) 7.5 Hz, 3H). 13C NMR (125
MHz, C6D6): δ 168.2, 53.6, 35.7, 25.1, 12.7, 17.1, 11.0.
Synthesis of N-Propyl-4-phenyl-2-butylamine (33a) [68164-01-
2]. In a glovebox, (η5-Me5C5)2SmCH(TMS)2 precatalyst (28.5 mg,
50 µmol), n-propylamine (59.1 mg, 1.0 mmol), 2-phenylmethylenecy-
clopropane (156 mg, 1.2 mmol), and C6D6 (1 mL) were loaded into a
storage tube equipped with a magnetic stir bar and J. Young valve.
The valve was then closed and the clear solution stirred for 24 h at
60 °C. Et2O (2 mL) was next added to the reaction mixture. The
resulting precipitate was filtered off through a pad of Al2O3 and washed
with Et2O (2 mL). The solvent was removed carefully in vacuo to yield
Synthesis of N-(4-Methylphenyl)-4-phenyl-2-butylamine (35a)
[289895-12-1]. In a glovebox, (η5-Me5C5)2LaCH(TMS)2 precatalyst
(28.5 mg, 50 µmol), p-toluidine (107 mg, 1.0 mmol), 2-phenylmeth-
ylenecyclopropane (156 mg, 1.2 mmol), and C6D6 (1 mL) were loaded
into a storage tube equipped with a magnetic stir bar and J. Young
valve. The valve was then closed and the clear solution stirred for 2
days at 60 °C. The reaction mixture was next added to a suspension of
ZnCl2 (136 mg, 1 mmol) and NaBH3CN (126 mg, 2 mmol) in THF
(5 mL). The resulting white suspension was stirred at room temperature.
After 20 h, the reaction mixture was filtered through a pad of Al2O3.
The solvent was removed in vacuo. Column chromatography on silica
gel (ethyl acetate-pentane, 1:22) afforded pure amine 35a (201 mg;
84% yield), Rf ) 0.46, and a diastereomeric mixture of syn-35b and
anti-35b (20 mg, 8% yield), Rf ) 0.49, as a colorless liquid.
1
crude imine 29a as a pale yellow liquid. H NMR (500 MHz, C6D6):
δ 7.17-7.11 (m, 5H), 3.09 (t, J ) 7.0 Hz, 2H), 2.92 (t, J ) 7.5 Hz,
2H), 2.37 (t, J ) 7.5 Hz, 2H), 1.73 (sextet, J ) 7.0 Hz, 2H), 1.42 (s,
3H), 0.99 (t, J ) 7.0 Hz, 3H). 13C NMR (125 MHz, C6D6): δ 166.8,
143.2, 129.2, 128.9, 126.3, 53.6, 44.3, 32.9, 25.1, 17.8, 12.8.
1
10% Pd/C (100 mg, 0.1 mmol) was added to the crude imine 29a
dissolved in anhydrous THF (2 mL), and the resulting suspension was
stirred under 1 atm of H2 at room temperature. After 2 days, the reaction
mixture was filtered through a pad of Al2O3. The solvent was removed
in vacuo. Column chromatography on silica gel (methylene chloride-
hexane-isopropylamine, 1:15:0.8) afforded pure amine 33a (168 mg;
Data for the major product 35a [289895-12-1], are as follows. H
NMR (500 MHz, C6D6): δ 7.16-7.13 (m, 5H), 7.03 (d, J ) 8.0 Hz,
2H), 6.97 (d, J ) 8.0 Hz, 2H), 6.38 (d, J ) 8.5 Hz, 2H), 3.23 (m, 1H),
2.61 (br s, 1H), 2.48 (t, J ) 7.0 Hz, 2H), 2.18 (s, 3H), 1.53 (dt, J ) 15
Hz, J ) 7.0 Hz, 1H), 1.45 (dt, J ) 15 Hz, J ) 7.0 Hz, 1H), 0.88 (d,
J ) 6.0 Hz, 3H). 13C NMR (125 MHz, C6D6): δ 144.2, 142.8, 130.5,
129.1, 129.0, 126.5, 126.4, 114.2, 48.4, 39.4, 33.1, 21.1, 20.9. Anal.
Calcd for C17H21N: C, 85.30; H, 8.84; N, 5.85. Found: C, 85.42; H,
8.97; N, 5.84; HRMS (m/z): calcd for C17H21N (M)+, 239.1669; found,
239.1666. LRMS (relative abundance): [M+ + 1] (25), [M+] (100),
238.2 (5), 225.1 (5), 224.1 (30), 216.9 (3), 211.9 (3).
1
88% yield), Rf ) 0.41. H NMR (500 MHz, C6D6): δ 7.23-7.10 (m,
5H), 2.63 (dt, J ) 9.5 Hz, 7.5 Hz, 2H), 2.41 (m, 1H), 1.68 (m, 1H),
1.58 (m, 1H), 1.42 (sextet, J ) 7.5 Hz, 2H), 0.99 (d, J ) 6.0 Hz, 3H),
0.92 (t, J ) 7.5 Hz, 3H). 13C NMR (125 MHz, C6D6): δ 143.5, 129.1,
128.9, 126.3, 53.1, 49.7, 39.9, 33.0, 24.1, 21.1, 12.5. Anal. Calcd for
C13H21N: C, 81.61; H, 11.06; N, 7.32. Found: C, 81.51; H, 11.21; N,
7.04.
Data for the minor products, a diastereomeric mixture of syn-35b
1
and anti-35b, are as follows. H NMR (500 MHz, C6D6): δ 7.15-
Synthesis of N-Phenyl-4-phenyl-2-butylamine (34a) [72641-00-
0]. In a glovebox, (η5-Me5C5)2LaCH(TMS)2 precatalyst (28.5 mg, 50
µmol), aniline (91 µL, 1.0 mmol), 2-phenylmethylenecyclopropane (156
mg, 1.2 mmol), and C6D6 (1 mL) were loaded into a storage tube
equipped with a magnetic stir bar and J. Young valve. The valve was
then closed and the clear solution stirred for 2 days at 60 °C. Et2O (2.0
mL) was next added to the reaction mixture. The resulting precipitate
was filtered off through a pad of Al2O3, and the pad was washed with
Et2O (2.0 mL). The solvent was removed carefully in vacuo to yield
crude imine 30a and 30b as a pale yellow liquid. A 10% Pd/C mixture
(100 mg, 0.1 mmol) was added to the crude imine 30a and 30b
dissolved in anhydrous THF (2.0 mL), and the resulting suspension
was stirred under 1.0 atm of H2 at room temperature. After 2 days, the
reaction mixture was filtered through a pad of Al2O3. The solvent was
removed in vacuo. Column chromatography on silica gel (ethyl acetate-
pentane, 1:22) afforded pure amine 34a (155 mg; 69% yield), Rf )
0.43, and a diastereomeric mixture of syn-34b and anti-34b (27 mg,
12% yield), Rf ) 0.46, as a colorless liquid.
6.94 (m, 14H), 6.41 (d, J ) 8.0 Hz, 4H), 3.50 (m, 1H), 3.44 (m, 1H),
3.00 (br s, 1H), 2.99 (br s, 1H), 2.82 (quintet, J ) 7.0 Hz, 1H), 2.74
(quintet, J ) 7.0 Hz, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.14 (d, J ) 7.0
Hz, 3H), 1.07 (d, J ) 7.0 Hz, 3H), 0.85 (d, J ) 7.0 Hz, 3H), 0.75 (d,
J ) 7.0 Hz, 3H). 13C NMR (125 MHz, C6D6): δ 146.2, 144.5, 144.0,
142.8, 130.6, 130.5, 129.0, 128.9, 128.8, 128.7, 127.0, 126.9, 126.5,
126.4, 114.4, 114.3, 54.2, 54.1, 44.5, 44.2, 21.2, 20.9, 18.7, 17.8, 17.7,
16.1.
Synthesis of N,N-Dimethyl-N′-(1-methyl-3-phenylpropyl)benzene-
1,4-diamine (36a). In a glovebox, (η5-Me5C5)2LaCH(TMS)2 precatalyst
(28.5 mg, 50 µmol), N,N-dimethyl-p-phenylenediamine (107 mg, 1.0
mmol), 2-phenylmethylenecyclopropane (156 mg, 1.2 mmol), and C6D6
(1 mL) were loaded into a storage tube equipped with a magnetic stir
bar and J. Young valve. The valve was then closed and the clear solution
stirred for 2 days at 60 °C. The reaction mixture was next added to a
suspension of ZnCl2 (136 mg, 1 mmol) and NaBH3CN (126 mg,
2 mmol) in THF (5 mL). The resulting white suspension was stirred at
room temperature. After 22 h, the reaction mixture was filtered through
a pad of Al2O3. The solvent was removed in vacuo. Column chroma-
tography on silica gel (ethyl acetate-pentane, 1:2) afforded pure amine
36a (150 mg; 56% yield) as a pale yellow liquid, Rf ) 0.40. 1H NMR
(500 MHz, C6D6): δ 7.16-7.13 (m, 3H), 7.06 (d, J ) 6.5 Hz, 2H),
6.71 (d, J ) 8.5 Hz, 2H), 6.48 (d, J ) 8.5 Hz, 2H), 3.24 (m, 1H), 2.58
Data for the major product 34a [72641-00-0] are as follows. 1H NMR
(500 MHz, C6D6): δ 7.16-7.12 (m, 4H), 7.05 (t, J ) 7.5 Hz, 1H),
7.01 (d, J ) 7.5 Hz, 2H), 6.72 (t, J ) 7.5 Hz, 1H), 6.39 (d, J ) 7.5
Hz, 2H), 3.20 (m, 1H), 2.88 (d, J ) 7.0 Hz, 1H), 2.46 (t, J ) 7.0 Hz,
2H), 1.50 (td, J ) 12.5 Hz, J ) 7.0 Hz, 1H), 1.43 (td, J ) 12.5 Hz,
9
J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003 12591

A R T I C L E S
Ryu et al.
Scheme 1. Proposed Catalytic Cycle for
Organolanthanide-Catalyzed Intermolecular Alkyne
Hydroamination
(s, 6H), 2.55 (t, J ) 8.0 Hz, 2H), 1.61 (m, 1H), 1.49 (m, 1H), 0.94 (d,
J ) 6.0 Hz, 3H). 13C NMR (125 MHz, C6D6): δ 144.8, 143.0, 140.9,
129.2, 129.0, 126.4, 116.6, 115.8, 49.3, 42.5, 39.6, 33.2, 21.5. Anal.
Calcd for C18H24N2: C, 80.55; H, 9.01; N, 10.44. Found: C, 80.52; H,
9.03; N, 10.35. HRMS (m/z): calcd for C18H24N2 (M+), 268.1934;
found, 268.1929. LRMS (relative abundance): [M+ + 1] (22), [M+]
(100), 266.9 (22, 263.9 (11), 256.2 (7), 253.1 (12), 247.9 (6), 243.9
(9), 235.9 (18), 231.9 (6).
Kinetic Studies of Hydroamination/Cyclization. In a typical
experiment, an NMR sample was prepared as described above (see
Typical NMR 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 or Unity-400 spectrometer, which had been
previously set to the appropriate temperature (T (0.2 °C; checked with
a methanol or ethylene glycol temperature standard). Data were acquired
using four scans per time interval with a long pulse delay (8 s) to avoid
signal saturation. The reaction kinetics were usually monitored from
the intensity changes in the substrate resonances and in the product
resonances over 3 or more half-lives on the basis of amine consumption.
The substrate concentration, C, was measured from the area, As,
standardized to the area Al of the free CH2(SiMe3)2 formed as turnover
commences. The CH2(SiMe3)2 is present as a result of quantitative
protonolytic ligand cleavage during catalyst generation. All data
collected could be convincingly fit by least squares to eq 6,
C ) mt + C0
(6)
(7)
Nt (h-1) ) -(60 min h-1)m
where C0 is the initial concentration of substrate (C0 ) As,0/Al,0). The
catalyst to substrate ratio was then accurately determined from the ratio
of As,0 and Al,0 or from the area of the product to A1. Accurate calibration
of catalyst and substrate concentrations was achieved with an internal
FeCp2 standard. The turnover frequency (h-1) was calculated from the
least-squares-determined slope (m) according to eq 7.
thermal tautomerization to the more stable imines,42 as shown
in Scheme 1. The intermolecular hydroamination reactions in
general proceed under an inert atmosphere at 60 °C under
conditions of excess alkene or alkyne (typically 50-250 [alkene/
alkyne]:[catalyst]; 10-50 [amine]:[catalyst] to minimize amine
inhibition)21a,b to >95% amine consumption. These catalytic
processes are conveniently monitored by the disappearance of
the amine NCH2 signal (δ ∼2.6-2.2 ppm) and/or by appearance
of the imine dNCH2 signal (δ ∼3.1-2.8 ppm) using 1H NMR
Results and Discussion
The principal goal of this study was the development of
catalytic intermolecular hydroamination methods which could
be generally applied to broad substrate classes: specifically,
closely related objectives involved defining the scope, regiose-
lectivity, effects of varying lanthanide ionic radius and ancillary
ligation, kinetics, and mechanism of organolanthanide-mediated
intermolecular hydroamination of aliphatic olefins, alkynes,
vinylarenes, divinylarenes, and methylenecyclopropanes. To
compare and contrast with the intramolecular cyclohydroami-
nation of aminoalkenes21 and aminoalkynes,22 as well as
bicyclizations involving both CtC and CdC functionalities,41
the present work focused on varying C-C unsaturation while
holding the amine and catalyst constant. The scope, regiose-
lectivity, and kinetic and mechanistic aspects of intermolecular
hydroamination of alkynes and vinylbenzenes are discussed first,
followed by intermolecular hydroamination coupled to subse-
quent cyclohydroamination of di- and trivinylbenzenes, and
finally, the hydroamination of methylenecyclopropanes.
1
spectroscopy. For paramagnetic Ln ) Nd, Sm, broadened H
NMR amine substrate and product resonances are observed
during catalytic turnover at room temperature and at 60 °C. This
behavior is analogous to the known coordination to/amine
exchange with paramagnetic LnNHR(NH2R)x amine-amido
complexes (vide infra).21b The known hydroamination products
were identified by comparison with literature data and/or data
of authentic samples. New compounds were characterized by
1H/13C and 2D NMR as well as by high-resolution mass
spectrometry. General product isolation procedures involve high-
vacuum transfer of the products, excess olefins or alkynes, and
other volatiles, followed by distillative removal of unreacted
olefins or alkynes, solvent, and CH2(SiMe3)2. A preparative-
scale reaction was carried out in a storage tube with the product
being isolated in 62% yield. All the products in NMR or
1
preparative-scale reactions were >95% pure by H NMR and
Scope and Regiochemistry of Intermolecular Hydroami-
nation of Alkynes, Alkenes, and Dienes. The complexes Cp′2-
SmCH(SiMe3)2 and Me2SiCp′′2LnCH(SiMe3)2 (Ln ) Nd, Sm,
Lu) effectively and regioselectively catalyze the intermolecular
hydroamination of a variety of alkenes and alkynes to yield the
corresponding amines and enamines, the latter of which undergo
GC-MS.
Intermolecular hydroamination results are summarized in
Table 1. It can be seen that the present organolanthanide-
centered process catalyzes a variety of alkene, alkyne, and diene
hydroaminations. Aliphatic (entries 1-3 and 5) and aromatic
(41) (a) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757-1771. (b) Li,
Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 707-708.
(42) Shainyan, B. A.; Mirskova, A. N. Russ. Chem. ReV. (Engl. Transl.) 1979,
48, 107-117 and references therein.
9
12592 J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003

Organolanthanide-Catalyzed Hydroamination
A R T I C L E S
Table 1. Intermolecular Hydroaminationa Results for Alkynes,
Alkenes, and Butadiene
disparity in rates between inter- and intramolecular processes
is likely greater for the same catalyst. A similar trend is also
observed in the conversion of 2-butyne/n-propylamine to N-(2-
butylidene)propylamine (entry 5, Nt ) 1, using Me2SiCp′′2Nd-
catalyst at 60 °C) vs that of 4-hexyn-1-amine to 2-ethyl-1-
pyrroline (Nt ) 96, using Cp′2Sm- catalyst at 21 °C).
In the case of unactivated aliphatic olefin hydroamination,
modest Nt values are observed for the intermolecular conversion
of 1-pentene + n-propylamine to N-propyl-1-methylbutylamine
(entry 8, eq 10) vs conversion of 4-penten-1-amine to 2-meth-
ylpyrrolidine (eq 11, n ) 1). It can be seen that under
comparable catalytic conditions, the intramolecular process can
be up to ∼350× more rapid (Nt ) 0.4 h-1 versus 140 h-1
,
a Me2SiCp′′2NdCH(SiMe3)2 as precatalyst. b NMR-scale reactions and
yield determined by 1H NMR and GC/MS after vacuum transfer of volatile
products. c Preparative-scale reactions and isolated yield.
respectively).
The above comparisons likely reflect the kinetic advan-
tages30,31 of intramolecular over intermolecular processes in both
olefinic and acetylenic hydroamination. However, these advan-
tages diminish with increasing ring size, due apparently to the
greater steric impediments to the CtC/CdC insertion and the
increasing loss of entropy in attaining the transition state30 for
the greater numbers of chain conformations. The intermolecular
alkyne processes are ∼3-7× more rapid than the corresponding
alkene transformations under identical reaction conditions (Table
1), in congruence with analogous intramolecular alkyne and
alkene comparisons.21,22 The greater alkyne insertion rates can
be associated with the sterically more accessible, cylindrical
CtC π system, more nucleophilic sp-hybridized carbon atoms,43
greater CtC π-donating capacity, greater thermodynamic
driving force, and greater stabilization of the insertive transition
state. The largest intermolecular (and intramolecular) alkyne
hydroamination rates are observed for silyl-substituted alkynes
(entries 1-3), and the reason likely reflects the known stabilizing
tendency by silicon substituents of R-carbanionic and â-car-
bocationic centers44 in what is a reasonable portrayal of the
insertive transition state (A). The proposed transition state A is
(entry 4) alkynes, aliphatic (entries 7 and 8) and trimethylsilyl-
substituted (entry 6) olefins, and a diene (entry 7) all undergo
intermolecular hydroamination to afford the corresponding
amines or enamines. Several features of the present intermo-
lecular catalytic transformation are especially noteworthy and
provide informative, useful quantitative parallels and contrasts
to the corresponding organolanthanide-catalyzed intramolecular
cyclohydroamination processes.21-24,41 The present process is
applicable not only to polarized olefins (entries 6 and 7) and
alkynes (entries 1-4) but also to nonpolarized olefins (entry 8)
and alkynes (entry 5) as well. In comparison to the correspond-
ing organolanthanide-catalyzed intramolecular hydroamination,
these intermolecular transformations are slower for both alkyne
and alkene substrates. For example, comparison of the Me2-
SiCp′′2Nd-catalyzed conversion of 1-phenylpropyne + n-
propylamine to N-(1-methyl-2-phenylethylidene)propylamine
(entry 4, eq 8) to the Cp′2Sm-catalyzed conversion of 5-phenyl-
also in accord with the observed regiochemistry, delivering the
lanthanide ion to the R-carbanionic position.
4-pentyn-1-amine to 2-benzyl-1-pyrroline (eq 9, n ) 1) under
comparable catalytic conditions (catalyst and substrate concen-
trations, solvent, temperature) reveals a decrease in Nt of
∼1400× (Nt ) 2 h-1 versus 2830 h-1, respectively). Since it
will be seen that the ring-bridged Nd catalyst is significantly
more active than the Cp′2Sm- catalyst (vide infra), the actual
(43) For a comparison of nucleophilic additions of alkenes and alkynes, see for
example: Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry, 3rd ed.; Harper & Row: New York, 1987; Chapter 7,
and references therein.
(44) (a) Bassindale, A. R.; Taylor, P. G. In The Chemistry of Organic Silicon
Compounds: Patai, S., Rappaport, Z., Eds.; Wiley: Chichester, U.K., 1989;
Chapter 14. (b) Fleming, I. In ComprehensiVe Organic Chemistry; Jones,
N. D., Ed.; Pergamon Press: Oxford, U.K., 1979; Chapter 13.
9
J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003 12593

A R T I C L E S
Ryu et al.
Table 2. Amine Substituent Group Effects on Turnover
The hydroamination results for trimethylsilyl- or phenyl-
substituted internal alkynes are examples of regioselective
insertion processes (entries 1-4). For example, for the trim-
ethylsilyl-substituted R-alkynes, N-alkyl-1-methyl-2-(trimeth-
ylsilyl)ethylimines are formed exclusively, as judged by in situ
NMR studies. These imines undergo subsequent, known 1,3-
sigmatropic silyl rearrangement45 under the catalytic reaction
conditions (rapidly brought to completion at higher tempera-
tures) to yield the more stable enamine-like structures (enties
1-3, eq 12). In the case of silyl-substituted R-olefins, only the
Frequencies for Intermolecular Hydroaminationa
R
N, h-1 b
t
CH3CH2CH2
CH3CH2CH2CH2
(CH3)2CHCH2
14
13
10
a Using Me2SiCp′′2NdCH(SiMe3)2 as precatalyst. Starting amine, alkyne,
and catalyst concentrations are identical in each experiment. b Turnover
frequencies measured in C7D8. The temperature was 60 °C in all cases.
complex (D). There is considerable precedent for such η3-allylic
insertion products in organo-f-element chemistry (e.g., eq
13).50,51
anti-Markovnikov addition product is observed (entry 6; N
delivered to the terminal carbon position).
The present hydroamination process for R-functionalized
olefins and alkynes likely involves significant stereoelectronic
control via metal-induced positive polarization of the evolving
carbon skeleton, which ultimately leads to olefin or alkyne
insertion products. The marked regioselectivity of the organo-
lanthanide-mediated R-functionalized olefin and alkyne hy-
droamination demonstrates that important factors other than
simple sterics are operative, as previously observed in organo-
lanthanide-mediated styrenic olefin and arylalkyne hydrosily-
lation.46 These kinetic and directing effects argue for SiMe3
activating effects known in organosilicon chemistry,44 i.e., a
â-Si-C bond interaction with the metal to stabilize the
electrophilic lanthanide center (e.g., B),20k as suggested by ab
initio calculations,47 as well as interaction of the electrophilic
lanthanide center with adjacent arene π systems (e.g., C).48,49
In the case of terminal alkynes, a previously characterized52
alkyne oligomerization process is considerably more rapid than
hydroamination and dominates the catalytic chemistry under the
conditions53 of Table 1.
With regard to amine substrate effects, the hydroamination
process slightly favors less sterically encumbered amines, with
Nt falling in the order n-propyl > n-butyl > isobutyl (Table 2)
for identical catalyst, alkyne, and reaction conditions. This likely
reflects steric demands during the alkyne insertion processes
(Scheme 1). With regard to catalyst effects, the reaction rate
for the present intermolecular process can be modulated
considerably by varying the lanthanide size and ancillary
ligation, as shown in Table 3. For example, under identical
amine, alkyne, and catalyst concentrations as well as reaction
temperature, increasing the Ln3+ ionic radius54 and opening the
(50) For related Cp′2Ln(η3-allyl)complexes, for examples, also see: (a) Topics
in Organometallic Chemistry; Kobayashi, S., Ed.; Springer: Berlin,
Germany, 1999; Vol. 2. (b) Edelmann, F. T. Top. Curr. Chem. 1996, 179,
247-276. (c) Evans, W. J.; Gonzales, S. L.; Ziller, J. W. J. Am. Chem.
Soc. 1994, 116, 2600-2608. (d) Evans, W. J.; Keyer, R. A.; Rabe, G. W.;
Drummond, D. K.; Ziller, J. W. Organometallics 1993, 12, 4664-4667.
(e) Scholz, A.; Smola, A.; Scholz, J.; Loebel, J.; Schimann, H.; Thiele, K.
H. Angew. Chem., Int. Ed. Engl. 1991, 30, 435-436. (f) Nolan, S. P.; Stern,
D.; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 7844-7853.
The insertion of a conjugated diene into the Ln-N bond is
also noteworthy. The results of the 1,3-butadiene hydroamination
illustrate that 1,4-addition is favored over 1,2-insertion (entry
7) and suggest a possible pathway involving an η3-crotyl
(51) (a) For diene insertion into Sc-H bonds, see: (a) Bunel, E.; Burger, B. J.;
Bercaw, J. E. J. Am. Chem. Soc. 1988, 110, 978-976. (b) For diene
insertion into Ln-C bonds, see ref 35.
(52) (a) Heeres, H. J.; Nijhoff, J.; Teuben, J. H. Organometallics 1993, 12,
2609-2617. (b) Evans, W. J.; Keyer, R. A.; Ziller, J. W. Organometallics
1993, 12, 2618-2633. (c) Heeres, H. J.; Teuben, J. H. Organometallics
1991, 10, 1980-1986 and references therein. (d) Heeres, H. J.; Meetsma,
A.; Teuben, J. H. Organometallics 1990, 9, 1508-1510. (e) Heeres, H. J.;
Meetsma, A.; Teuben, J. H.; Rogers, R. D. Organometallics 1989, 8, 2637-
2646. (f) Den Haan, K. H.; Wielstra, Y.; Teuben, J. H. Organometallics
1987, 6, 2053-2060.
(45) For examples of 1,3-silyl rearrangement from C to N, see: (a) Hitchcock,
P. B.; Lappert, M. F.; Liu, D.-S. J. Chem. Soc., Chem. Commun. 1994,
1699-1700. (b) Brook, A. G.; Bassindale, A. R. In Rearrangements in
Ground and Excited States; de Mayo, P., Ed.; Academic Press: New York,
1980; Vol. 2, pp 204-205. (c) Bassindale, A. R.; Brook, A. G. Can. J.
Chem. 1974, 52, 3474-3483. (d) Belavin, I. Yu.; Fedoseeva, N. A.; Baukov,
Yu. I.; Lutsenko, I. F. J. Gen. Chem. USSR (Engl. Transl.) 1973, 43, 443.
(46) (a) Molander, G. A.; Romero, J. A. C.; Corrette, C. P. J. Organomet. Chem.
2002, 647, 225-235. (b) Fu, P.-F.; Brard, L.; Li, Y.; Marks, T. J. J. Am.
Chem. Soc. 1995, 117, 7157-7168.
(47) Koga, N.; Morokuma, K. J. Am. Chem. Soc. 1988, 110, 108-112.
(48) For ηn-benzylic structures, see: (a) Evans, W. J.; Ulibarri, T. A.; Ziller, J.
W. J. Am. Chem. Soc. 1990, 112, 219-223. (b) Mintz, E. A.; Moloy, K.
G.; Marks, T. J.; Day, V. W. J. Am. Chem. Soc. 1982, 104, 4692-4695.
(49) For arene-lanthanide complexes, see: Bochkarev, M. N. Chem. ReV. 2002,
102, 2089-2117.
(53) For terminal alkynes HCtCR (R ) n-butyl, Ph, SiMe3), the typical catalytic
reaction was carried out by the following procedure. Under an Ar
atmosphere, a mixture of Me2SiCp′′2NdCH(SiMe3)2 (3.0 mg, 5.0 µmol),
1-hexyne (75.2 Mg, 915.0 µmol), and n-propylamine (3.1 mg, 52.4 µmol)
in 0.60 mL of C6D6 was heated at 60 °C while being monitored by 1H
NMR. The 1H/13C NMR and GC/MS results indicate 2-butyl-1-octen-3-
yne as the major product (96%) along with other unidentified minor
1
products. The yield was estimated by H NMR and GC/MS after vacuum
transfer of the volatile products. The product NMR spectroscopic data agree
well with the literature data: Straub, T.; Haskel, A.; Eisen, M. S. J. Am.
Chem. Soc. 1995, 117, 6364-6365.
(54) Shannon, R. D. Acta Crystallogr. 1976, 32, 751-760.
9
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Organolanthanide-Catalyzed Hydroamination
A R T I C L E S
Table 3. Metal and Ancillary Ligand Effects on Turnover
Frequencies for Intermolecular Hydroaminationa
catalyst
Cp′2Sm-
Me2SiCp′′2Lu-
Me2SiCp′′2Sm-
Me2SiCp′′2Nd-
N, h-1 b
t
0.01
0.1
4
14
a Starting amine, alkyne, and catalyst concentrations are identical in each
experiment. b Turnover frequencies measured in C7D8. The temperature is
60 °C in all cases.
Figure 2. Plot of observed reaction rate vs alkyne concentration for the
intermolecular hydroamination of MeCtCSiMe3 with NH2CH2CH2CH2-
CH3 using Me2SiCp′′2NdCH(SiMe3)2 as the precatalyst in toluene-d8. The
line represents the least-squares fit to the data points.
Figure 1. Plot of amine concentration vs time for the intermolecular
hydroamination of MeCtCSiMe3 with NH2CH2CH2CH2CH3 using Me2-
SiCp′′2NdCH(SiMe3)2 as the precatalyst in toluene-d8. The line represents
the least-squares fit to the data points.
metal coordination sphere by connecting the ancillary π-ligands
(Cp′2Ln f Me2SiCp′′2Ln) enhances the turnover frequency (Nt)
for the hydroamination of 1-(trimethylsilyl)propyne with n-
propylamine from 0.01 h-1 using Cp′2Sm as a catalyst to 0.1,
4, and 14 h-1 using Me2SiCp′′2Lu-, Me2SiCp′′2Sm-, and Me2-
SiCp′′2Nd-, respectively, as the catalyst. Such tendency for
larger metal ions and more open coordination spheres to
accelerate carbon-carbon multiple bond insertion into Ln-N
bonds is in accord with observations made in organolanthanide-
mediated intramolecular amino-olefin hydroamination21 and
amino-alkyne-alkene bicyclization.41 It likely reflects the steric
demands accompanying unsaturated carbon-carbon bond inser-
tion at the lanthanide center.
Figure 3. Plot of observed reaction rate vs catalyst concentration for the
intermolecular hydroamination of MeCtCSiMe3 with NH2CH2CH2CH2-
CH3 using Me2SiCp′′2NdCH(SiMe3)2 as the precatalyst in toluene-d8. The
line represents the least-squares fit to the data points.
> 10:1, Figure 2) and the concentration of catalyst precursor
varied over a 17-fold concentration range (Figure 3) indicate
that the reaction rate is first-order in alkyne and catalyst. Taken
together, the empirical rate law is given in eq 14, which stands
υ ) k[amine]0[alkyne]1[Sm]1
(14)
in stark contrast to the zero-order amine substrate kinetics
observed for both organolanthanide-catalyzed amino-olefin21
and amino-alkyne intramolecular cyclohydroamination.22 In
both these cases, turnover-limiting alkyne and alkene insertion
is inferred from these results and other evidence (vide infra).
The present results suggest a similar turnover-limiting step
involving intermolecular unsaturated carbon-carbon bond
insertion into the Ln-N bond. For the intermolecular process,
the rate of hydroamination decreases as the conversion progresses
beyond ∼90%, which is consistent with some competitive
catalyst inhibition by enamine or imine product coordination
(vide infra).12c,21b
Variable-temperature studies of the intermolecular hydroami-
nation of 1-(trimethylsilyl)propyne and n-propylamine mediated
by Me2SiCp′′2NdCH(SiMe3)2 were performed by 1H NMR, as
discussed in the kinetic study above. Results are summarized
in Figure 4. Standard Eyring (Figure 5) and Arrhenius analyses
(Figure 6) derived from the kinetic data afford the following
Kinetics and Mechanism of Intermolecular Hydroamina-
tion. Quantitative kinetic studies of the Me2SiCp′′2Nd-catalyzed
hydroamination of 1-(trimethylsilyl)propyne with n-butylamine
1
at 60 °C were carried out by in situ H NMR. Initially, the
catalyst concentration was held constant, the alkyne to amine
molar ratio was held at greater than 12:1 (the excess alkyne
concentration not only maintains approximately zero-order
conditions but also minimizes amine inhibition), the amine to
catalyst ratio was held at 15-20:1, and amine was monitored
until >90% consumption. The disappearance of 1H resonances
of the NCH2 (δ ∼2.3 ppm) in the amine and appearance of
dNCH2 (δ ∼3.3 ppm) in the imine product were normalized
to an internal CH2(SiMe)3 standard. The kinetic data shown in
Figure 1 reveal a linear dependence of amine concentration on
reaction time over a ∼15-fold concentration range, which agrees
with an essentially zero-order dependence of the catalytic rate
on amine concentration. Kinetic plots for the catalytic reaction
rate as a function of alkyne concentration (varied over a 3-fold
concentration range; [alkyne]:[amine] > 12:1, [amine]:[catalyst]
(55) (a) Benson, S. W. ThermochemicalKinetics, 2nd ed.; Wiley: New York,
1986; pp 8-10. (b) Robinson, P. J. J. Chem. Educ. 1978, 55, 509-510.
9
J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003 12595

A R T I C L E S
Ryu et al.
Table 4. Activation Parameter Comparison for Intermolecular
Hydroamination and Intramolecular Hydroamination/Cyclization
Reactions
Figure 4. Normalized ratio of amine to lanthanide concentration as a
function of time and temperature for the intermolecular hydroamination of
MeCtCSiMe3 with NH2CH2CH2CH2CH3 using Me2SiCp′′2NdCH(SiMe3)2
as the precatalyst in toluene-d8. Starting amine, alkyne, and catalyst
concentrations are held constant. The line represents the least-squares fit
to the data points.
a Determined using Me2SiCp′′2NdCH(TMS)2 in toluene-d8. b Determined
using Me2SiCp′′2SmCH(TMS)2 in o-xylene-d10.21f c Determined using
Cp′2LaCH(TMS)2 in toluene-d8.23a d Determined using Cp′2LaCH(TMS)2
in toluene-d8.21b e Determined using Cp′2SmCH(TMS)2 in toluene-d8.22a
18.5 (2.0) kcal/mol.21f In these cases, the intramolecular
processes proceed with substantially lower activation enthalpies
and activation energies than the intermolecular process, except
in the case of intramolecular internal amino-olefin processes
suffering significant electrostatic and steric impediments;21f
however, the large, negative ∆Sq values are interestingly
comparable in both cases of intramolecular and intermolecular
processes. This argues that the intramolecular processes do not
benefit from major activation entropic advantages and that the
transition states are all highly organized/constrained.
Further mechanistic evidence for steric constraints in the
transition state for intermolecular hydroamination derives from
metal/ancillary ligand effects on the rate of the Me3SiCtCMe
+ n-propylamine reaction (Table 3). A pattern of decreasing
Nt with a more constricting metal coordination sphere is seen
here with Nt(60 °C) ) 14 h-1(Me2SiCp′′2Nd-) > 4 h-1 (Me2-
SiCp′′2Sm-) > e0.1 h-1 (Me2SiCp′′2Lu-) > e0.01 h-1 (Cp′2-
Sm) and is observed for numerous other organolanthanide-
catalyzed processes where olefin insertion is the turnover-
limiting step.21b,e,f,41 Interestingly, the only significant exception
to this pattern is in the intramolecular amino-alkyne cyclohy-
droamination. Additional support for steric impediments in the
present intermolecular process is found in RNH2 substituent
effects, where Nt declines in the order n-Pr > n-Bu > i-Bu in
the reaction with Me3SiCtCMe (Table 2).
Figure 5. Eyring plot for the intermolecular hydroamination of MeCt
CSiMe3 with NH2CH2CH2CH2CH3 using Me2SiCp′′2NdCH(SiMe3)2 as the
precatalyst in toluene-d8. The line represents the least-squares fit to the
data points.
With regard to the proposed mechanism of the present
organolanthanide-mediated intermolecular hydroamination
(Scheme 1), the first step appears to be analogous to that
proposed for intramolecular hydroamination.21-24 The proto-
nolytic reaction of organolanthanide Cp′2LnCH(SiMe3)2 and
Me2SiCp′′2LnCH(SiMe3)2 complexes with amines generates the
catalytically active species. The products are likely amine-
amido adducts, which would be expected to undergo rapid bound
amine-amido exchange as well as rapid bound-free amine
exchanges, as found in intramolecular amino-olefin21 and
amino-alkyne22 cyclohydroaminations. The second step in this
catalytic process most likely involves turnover-limiting inter-
molecular alkyne or alkene insertion into the resulting Ln-N
bonds via well-documented insertive transition states21b as
Figure 6. Arrhenius plot for the intermolecular hydroamination of MeCt
CSiMe3 with NH2CH2CH2CH2CH3 using Me2SiCp′′2NdCH(SiMe3)2 as the
precatalyst in toluene-d8. The line represents the least-squares fit to the
data points.
activation parameters: ∆Hq ) 17.2(1.1) kcal/mol, ∆Sq ) -25.9-
(9.7) eu, and Ea ) 17.8(1.8) kcal/mol,55 Similar analyses for
intramolecular amino-olefin cyclohydroamination (Table 4,
entry 4) yield ∆Hq ) 12.7(1.4) kcal/mol, ∆Sq ) -27.0(4.6)
eu, and Ea ) 13.4(1.5) kcal/mol,21b while for 4-pentyn-1-amine
cyclohydroamination (Table 4, entry 5) ∆Hq ) 10.7(1.8) kcal/
mol, ∆Sq ) -27.4(11.9) eu, and Ea ) 11.3(2.0) kcal/mol22a
and for 2,2-dimethyl-hept-4-enylamine (Table 4, entry 2)
∆Hq ) 17.7 (2.1) kcal/mol, ∆Sq ) -24.7 (5) eu, and Ea )
9
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Organolanthanide-Catalyzed Hydroamination
A R T I C L E S
Table 5. Organolanthanide-Catalyzed Intermolecular
purified by recrystallization. Alternatively, the free amine
products can be isolated from the reaction mixture by column
chromatography.
Hydroamination of Vinylarenesa
The scope of organolanthanide-mediated intermolecular hy-
droamination of vinylarenes is summarized in Table 5. Cp′2-
LaCH(SiMe3)2 catalyzes the hydroamination of a variety of
vinylarenes, and this process is compatible with polar functional
groups such as -F (entry 4), -CF3 (entry 5), -OMe (entry 6),
-NMe2 (entry 7), and -SMe (entry 8). However, when a
strongly coordinating substrate, 4-vinylpyridine, is added to a
catalyst solution (entry 9), instant precipitation57 is observed.
With regard to substituent effects, in general electron-donating
substituents decrease turnover frequencies (entry 1 vs entries
2, 4, 6, and 7). Weakly electron-donating methyl substitution
and π-donating fluorine substitution exhibit slightly decreased
Nt’s compared to styrene, whereas the strongly electron-donating
methoxy and dimethylamino substituents exhibit significantly
decreased Nt’s. In contrast, electron-withdrawing trifluoromethyl
substitution exhibits a significantly enhanced Nt (entry 2 vs 5).
Most likely, N-H bond insertion across electron-rich styrenic
olefin is hampered by electrostatic repulsion between the
nitrogen lone pair electrons and the π electrons of the styrenic
olefin. Therefore, decreased styrenic olefin electron density
lowers the barrier to insertion into Ln-N. The present orga-
nolanthanide-catalyzed intermolecular process is broad in scope,
from electron-deficient styrenes to electron-rich styrenes, com-
pared to the Pd-catalyzed hydroamination of vinylarene, in
which the scope encompasses only electron-deficient and
electron-neutral styrenes.10
Organolanthanide-mediated intermolecular vinylarene hy-
droamination proceeds in good isolated yields and excellent
regioeselectivities to afford anti-Markovnikov products. 1H
NMR spectra of completed in situ monitored experiments exhibit
only resonances attributable to the addition product and excess
olefin, with no detectable traces of regioisomers except (∼4%)
in the case of (trifluoromethyl)styrene (Table 5, entry 5). As
noted before, these regiochemical preferences are reasonably
attributed to aryl-directing interactions46,49 of the weakly
coordinating arene π system and the electrophilic lanthanide
center (Scheme 2, T1). Weakly Lewis basic arene π electrons
stabilize the electron-deficient Lewis acidic lanthanide center
and deliver lanthanide to the benzylic position. There is
substantial precedent for ηn-benzylic structures in organo-f-
element chemistry46 and for the 2,1-addition of organolanthanide
center to styrenic olefins.46,58 Such processes are favored by
sterically open metal coordination spheres,46b and lanthanide
ion delivery is biased to the benzylic position by stereoelectronic
factors other than simple sterics. With regard to substitution
effects on regioselectivity, the intermolecular hydroamination
of electron-deficient vinylarenes (Table 5, entry 5) proceeds,
a Turnover frequencies (Nt) measured in C7D8. NMR reaction conditions:
[cat]:[amine]:[vinylarene] ) 1:10:100 employed for pseudo-zero-order
kinetic plot; [cat] ) 0.03 mΜ. b Isolated yield in preparative-scale reaction:
the reactions were conducted in C6D6. Preparative reaction conditions: [cat]:
[amine]:[vinylarene] ) 1:20:40 employed; [cat] ) 0.05 mΜ. c Isolated yield
of the corresponding HCl salt in preparative-scale reaction. d [anti-Mark-
ovnikov]:[Markovnikov] ) 96:4 regiochemistry was observed.
discussed above, to yield metal-alkyl or metal-alkenyl com-
plexes which then undergo rapid intra- or intermolecular
protonolysis with amine moieties, generating the corresponding
amine or enamine products and regenerating the catalysts as
depicted in Scheme 1.
Intermolecular Hydroamination of Vinylarenes. Organo-
lanthanide-catalyzed intermolecular hydroamination of most
vinylarenes proceeds under an inert atmosphere at 90 °C. All
of the NMR-scale reactions were carried out under identical
reaction conditions in order to compare the relative reactivities.
In addition, an [olefin]:[amine]:[catalyst] ratio of 100:10:1 was
employed to minimize amine inhibition and to shorten reaction
times. Turnover frequencies were determined over 3 half-lives
in toluene-d8 at 90 °C from the slope of the kinetic plots of
[substrate]/[catalyst] vs time. All reactions in Table 5 exhibit
pseudo-zero-order kinetic behavior in the presence of excess
vinylarene. The relative reactivities of vinylarenes can be
compared by Nt. Preparative-scale reactions were carried out
in sealed tubes at 90 °C, employing a 40:20:1 ratio of [olefin]:
[amine]:[catalyst]. Less than 5 mol % of precatalyst and a slight
excess (1.2-1.5 equiv) of olefin suffice for practical reaction
rates.56 The final phenethylamine products were worked up by
filtration through a short plug of Al2O3 and treated with
anhydrous HCl‚Et2O. The resulting amine-HCl salts were
(56) Due to the polymerization properties of styrene derivatives, a small excess
of styrene derivatives was employed. In situ NMR monitoring confirmed
the complete consumption of n-propylamine in the reaction with 1.2-1.5
equiv of styrenes.
(57) For known lanthanide-pyridine complexes, see: (a) Berg, D. J.; Boncella,
J. M.; Andersen, R. A. Organometallics 2002, 21, 4622-4631. (b) Schultz,
M.; Boncella, J. M.; Berg, D. J.; Tilley, T. D.; Andersen, R. A.
Organometallics 2002, 21, 460-472. (c) Clark, D. L.; Gordon, J. C.; Scott,
B. L.; Watkin, J. G. Polyhedron 1999, 18, 1389-1396. (d) Den Haan, K.
H.; Teuben, J. H. J. Organomet. Chem. 1987, 322, 321-329. (e) 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.
(58) Molander, G. A.; Schmitt, M. H. J. Org. Chem. 2000, 65, 3767-3770.
9
J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003 12597

A R T I C L E S
Ryu et al.
Scheme 2. Proposed Catalytic Cycle for Organolanthanide-Catalyzed Intermolecular Vinylarene Hydroamination
as noted above, in slightly decreased regioselectivity (96:4 anti-
Markovnikov product:Markovnikov product), while electron-
rich and electron-neutral vinylarenes provide exclusively aniti-
Markovnikov products. Most likely, the highly electron-
withdrawing -CF3 functionality decreases the electron density
in the arene π system, resulting in lessened arene coordinative
tendencies.
Intermolecular Hydroamination/Cyclization of Divinyl/
Trivinylarenes. In comparison with intramolecular hydroami-
nation, one of the advantages of intermolecular hydroamination
is the facile and concise synthesis of amine-containing, syntheti-
cally useful structures from commercially available substrates
or from readily synthesized substrates. This advantage is
illustrated by the synthesis of tetrahydroisoquinolines (THIQs)
by intermolecular hydroamination coupled with subsequent
cyclization.
lation of chiral formamidines,65 organolithium additions to
imines followed by condensation,66 and metal-catalyzed cy-
clization reactions.67 These synthetic methods permit the
synthesis of 1-substituted THIQ in two steps: cyclization and
creation of the stereocenter. However, only the Pictet-Spengler
approach creates the stereogenic carbon at C-1 concurrent with
ring closure. In contrast to these results, organolanthanide-
catalyzed intermolecular hydroamination + subsequent cycliza-
tion of divinylbenzene affords the THIQ structure in a single
step, while creating a stereogenic center at the C-1 position.
The success of the present process is based on the excellent
regioselectivity of the intermolecular vinylarene hydroamination
described above. Regioselective Ln-N bond insertion into the
styrenic CdC functionality through aryl-directed 2,1-addition
provides the anti-Markovnikov product in excellent yield, and
this process is efficiently coupled with intramolecular cyclo-
hydroamination of the phenylethylamine intermediate (eq 15).
Tetrahydroisoquinolines (THIQs) are of great interest, due
to their interesting biological and pharmaceutical properties. For
instance, 1-MeTHIQ,59 an endogenous Parkinsonism-preventing
substance,60 is involved in the treatment of nerve diseases, and
some THIQ family natural products include potent cytotoxic
agents that display a range of antitumor and antimicrobial
activities.61 The substantial literature on this class of hetero-
cycles reflects their importance. Notable synthetic methods
include the Pictet-Spengler cyclization,62 the reduction of 3,4-
dihydroisoquinolines,63 the Pomeranz-Fristch reaction,64 R-alky-
The polyvinylarene intermolecular hydroamination plus sub-
sequent cyclization results are summarized in Table 6. In
(63) (a) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael, Y. W. Org.
Lett. 2000, 2, 3901-3903. (b) Comins, D. L.; Badawi, M. M. Heterocycles
1991, 32, 1869-1873. (c) Polniaszek, R. P.; Dillard, L. W. Tetrahedron
Lett. 1990, 31, 797-800. (d) Polniaszek, R. P.; Kaufman, C. R. J. Am.
Chem. Soc. 1989, 111, 4859-4863.
(64) (a) Schlosser, M.; Simig, G.; Geneste, H. Tetrahedron 1998, 54, 9023-
9032. (b) Kaufman, T. S. J. Chem. Soc., Perkin Trans. 1 1996, 2497-
2505.
(65) (a) Meyers, A. I.; Dickman, D. A. J. Am. Chem. Soc. 1987, 109, 1263-
1265. (b) Meyers, A. I.; Warmus, J. S.; Gonzalez, M. A.; Guiles, J.;
Akahane, A. Tetrahedron Lett. 1991, 32, 5509-5512. (c) Meyers, A. I.
Tetrahedron 1992, 48, 2589-2612.
(66) Wunsch, B.; Nerdinger, S. Eur. J. Org. Chem. 1998, 711-718.
(67) (a) Richter-Addo, G. B.; Knight, D. A.; Dewey, M. A.; Arif, A. M.; Gladysz,
J. A. J. Am. Chem. Soc. 1993, 115, 11863-11873. (b) Wirth, T.; Fragale,
G. Synthesis 1998, 162-166.
(59) For a review on asymmetric synthesis of 1-substituted tetrahydroisoquino-
lines, see: Rozwadowska, M. D. Heterocycles 1994, 39, 903-931 and
references therein.
(60) (a) Abe, K.; Taguchi, K.; Wasai, T.; Ren, J.; Utsunomiya, I.; Shinohara,
T.; Miyatake, T.; Sano, T. Brain Res. Bull. 2001, 56, 55-60. (b) Parrado,
J.; Absi, E.; Ayala, A.; Castano, A.; Cano, J.; Machado, A. J. Neurochem.
2000, 75, 65-71.
(61) Scott, J. D.; Williams, R. M. Chem. ReV. 2002, 102, 1669-1730.
(62) Whaley, W. M.; Govindachari, T. R. Organic Reactions; Wiley: New York,
1951; Vol. 6, p 151.
9
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Organolanthanide-Catalyzed Hydroamination
A R T I C L E S
Table 6. Organolanthanide-Catalyzed Intermolecular
Hydroamination of Di- and Trivinylarenes
the intermolecular hydroamination is relatively slow, a signifi-
cant portion of the catalyst may be tied up in the first
intermolecular catalytic cycle and therefore delay initiation of
the second intramolecular catalytic cycle (vide infra).
The intermolecular hydroamination followed by subsequent
bicyclization of trivinylbenzene (Table 6, entry 3) is especially
noteworthy. Intermolecular hydroamination proceeds chemose-
lectively, only at the â-ïlefin moiety rather than at the sterically
hindered R olefin (eq 17). La-NHR bond addition to an R-ïlefin
a Turnover frequencies (Nt) measured in C7D8. NMR reaction conditions:
[cat]:[amine]:[vinylarene] ) 1:10:100 employed for pseudo-zero-order
kinetic plot; [cat] ) 0.03 mΜ. b Isolated yield of free amine in preparative-
scale reaction. Preparative reaction conditions: [cat]:[amine]:[vinylarene]
) 1:20:40 employed; [cat] ) 0.05 mΜ.
comparison to the corresponding organolanthanide-catalyzed
intermolecular hydroamination of vinylarenes, notably enhanced
Nt’s in intermolecular hydroamination of divinylarenes are
observed under identical reaction conditions. For example,
comparison of the Cp′2La-catalyzed intermolecular hydroami-
nation of n-propylamine and styrene (Table 5, entry 1) to the
Cp′2La-catalyzed intermolecular hydroamination of n-propy-
lamine and divinylbenzene (Table 6, entry 1) under comparable
catalytic conditions reveals a substantial increase in Nt (Nt ) 2
h-1 versus 11 h-1). Presumably, additional electron-withdrawing
alkene substitution at the ortho position decreases the electron
density at the other olefin and reduces the electrostatic repulsion
between the Ln-N and CdC functionalities. The rate enhance-
ment for vinylnaphthalene (Table 5, entry 3) versus divinyl-
naphthalene (Table 6, entry 2) is consistent with this trend. This
effect is particularly significant in the intramolecular cyclization
of the intermediate 2-ethenylphenethylamines: Nt ) 8.0 h-1
for 17 (Table 6, entry 1) versus Nt ) 22.2 h-1 for 21 (Table 6,
entry 3).
having two ortho substituents is efficiently blocked. After the
rapid protonolysis of the Ln-C bond by n-propylamine, only
the single intermediate 21 is observed by 1H NMR. The ensuing
intramolecular cyclization of 21 likely affords Ln-C species
H by analogy to the transformation of divinylbenzene 17 f
18. The intramolecular cyclization is observed by 1H NMR after
>70% consumption of the n-propylamine (vide infra). There-
fore, the Ln-C bond protonolysis of H by n-propylamine is
efficiently prevented, due to the low n-propylamine concentra-
tion. In addition, the Ln-C bond protonolysis of H by the
sterically hindered secondary amine intermediate 21 is moder-
ately slow68 compared to the sequential second cyclization,
which affords the hexahydrocyclopent[ij]isoquinoline species
22. In contrast to the previously reported41 bicyclization of
aminodiene J (eq 18), which provided a cis/trans product
mixture, the present intermolecular hydroamination/bicyclization
of trivinylbenzene proceeds with excellent diastereoselectivity.
As shown above, the intermolecular hydroamination of
alkynes follows the empirical rate law υ ) k[amine]0[alkyne]1-
[catalyst]1, while intramolecular cyclohydroamination of ami-
noalkenes follows the empirical rate law υ ) k[aminoalkene]0-
[catalyst]1. Therefore, in principle, the rate of intermolecular
hydroamination should vary with divinylarene concentration,
while the subsequent cyclization should be independent of
divinylarene concentration and intermediate phenethylamine
concentration. However, when lower divinylbenzene concentra-
tions (∼0.6 M vs 3.0 M) are employed with the identical initial
amine and catalyst concentrations ([DVB]:[PA]:[catalyst] )
20:10:1), the turnover frequencies of both the first addition
and the cyclization decrease from 11 to 2.1 h-1 and from 8.0 to
1.1 h-1, respectively (eq 16). Presumably, in the case where
(68) (a) In general, Ln-C protonolysis for Cp′2La-CH(SiMe3)2 by diethylamine
requires ∼2 h at 60 °C. (b) For the organolanthanide-catalyzed tandem
bicyclizations of secondary amino dienes, amino diynes, and amino enynes,
see ref 41.
9
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A R T I C L E S
Ryu et al.
Scheme 3. Proposed Stereochemical Pathways for Organolanthanide-Catalyzed Intramolecular Hydroamination/Ensuing Cyclization of
Trivinylbenzene and n-Propylamine To Afford trans-(()-1-Methyl-3-propyl-1,2,2a,3,4,5-hexahydro-3-azaacenaphthylene (22)
1H NMR spectra and GC/MS spectra of completed in situ
monitored experiments shows only resonances attributable to
the trans isomer. The stereochemical and conformational as-
signments of 22 were supported by rigorous one- and two-
dimensional NMR experiments (see the Experimental Section).
The diastereoselectivity can be understood by an analogy to
the cyclohydroamination of R-substituted amino-olefins,21
R-substituted amino-allenes,23 and R-substituted amino-diene24
(Scheme 3).
An attempt was also made to effect the catalytic intermo-
lecular hydroamination of divinylveratrole K to the correspond-
ing tetrahydroisoquinoline (eq 19). However, it was not
Figure 7. Normalized ratios of intermediate to lanthanide and of product
to lanthanide concentration as a function of time and temperature for the
intermolecular hydroamination plus ensuing cyclohydroamination of 2,3-
divinylnaphthalene and n-propylamine using Cp′2LaCH(SiMe3)2. The lines
represent least-squares fits to the data points for the second half-life of the
reaction. After 70% conversion, the intermediate 19 resonance overlapped
with the product 20 resonance.
by 1H NMR spectroscopy. The divinylarene:amine:catalyst
molar ratio was held at 100:10:1. The decrease of the NCH2
(δ ∼2.5 ppm) resonance in the n-propylamine, the increase of
the MeCH2CH2NH (δ ∼1.4 ppm) resonance in the intermediate
phenethylamine, and the H resonance at the C1 position
(∼δ 3.8 ppm) in the THIQ product were monitored over time
and normalized versus the CH2(SiMe3)2 internal standard
(δ ∼0.05 ppm). The kinetic plot of Figure 7 reveals ap-
proximately zero-order behavior in the intermolecular hy-
droamination step in the presence of excess divinylarene.
Intermediate 19 is generated with consumption of propylamine,
and the cyclized product 20 begins to appear after ∼70%
consumption of n-propylamine and ∼70% generation of inter-
mediate 19. The ensuing intramolecular cyclization of the
intermediate occurs, before the intermolecular hydroamination
of propylamine and divinylbenzene is complete, after ap-
proximately 2 half-lives. Scheme 4 illustrates the proposed
mechanistc pathway based on the kinetic studies. Rapid pro-
tonolysis of the Cp′2La-CH(SiMe3)2 bond by n-propylamine
produces CH2(SiMe3)2 and generates the lanthanide-amido
complex 23. Subsequent olefin insertion via a four-centered
transition state (T3) affords the lanthanide-alkyl species 24.
This intermediate is quickly protonolyzed by n-propylamine and
successful, due to the high competing polymerization reactivity
of K. The substrate was rapidly polymerized under typical
catalytic reaction conditions, and ∼68% conversion to inter-
mediate phenethylamine L, which could not be isolated from
1
polymeric byproducts, was observed during in situ H NMR
experiments.
Quantitative kinetic studies of the Cp′2La-catalyzed reaction
of divinylarenes with n-propylamine at 90 °C were carried out
9
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Organolanthanide-Catalyzed Hydroamination
A R T I C L E S
Scheme 4. Proposed Catalytic Cycle for Organolanthanide-Catalyzed Intermolecular Hydroamination plus Subsequent Cyclohydroamination
of Divinylarenes
regenerates the lanthanide-amido complex 23. The direct
addition of Ln-C to the styrenic olefin of 24 without pro-
tonolysis does not occur, presumably due to unfavorable strain
energies associated with formation of a four-membered ring.
As the concentration of the phenethylamine intermediate 17
bearing a styrenic olefin functionality increases, protonolysis
by intermediate 17 competes with the protonolysis by n-
propylamine. Thus, the increased concentration of the interme-
diate 17 favors the formation of the lanthanide-amido complex
25, and the second catalytic cycle begins to turnover before
complete consumption of n-propylamine. Styrenic olefin inser-
tion via a four-centered transition state into the Ln-N bond of
25 affords the corresponding lanthanide-alkyl complex 26.
Subsequent protonolysis by n-propylamine and/or intermediate
17 releases the final THIQ product 18.
Intermolecular Hydroamination of Methylenecyclopro-
panes. Although methylenecyclopropanes (MCPs)69 are highly
strained, they are remarkably stable and readily accessible
molecules that have served as versatile building blocks in
organic synthesis.70 The release of strain energy associated with
the cleavage of a cyclopropane ring results in driving force in
numerous organic transformations. Especially, increasing at-
tention has been paid to the transition-metal-catalyzed reactions
of MCPs,71 which have been employed for construction of a
number of complex organic molecules.70 Organolanthanide-
mediated MCP transformations72 represent one notable class of
reactions. We show here that MCPs also can serve as starting
materials in organolanthanide-mediated intermolecular hy-
droamination processes.
The organolanthanide complexes Cp′2LnCH(SiMe3)2 (Ln )
La, Sm) mediate the intermolecular hydroamination of MCP to
the corresponding enamine, which undergoes subsequent tau-
tomerization to the more stable imine42 (eq 20). Subsequent
hydrogenation of the initially formed imine with 10 mol % Pd/C
or NaBH3CN-ZnCl273,74 affords the corresponding amines. The
intermolecular hydroamination results for symmetrical MCPs
(entry 1) and unsymmetrical MCPs (entries 2-5) are shown in
Table 7. This intermolecular process is not restricted to aliphatic
amines (Table 7, entries 1 and 2) and is also applicable to aro-
matic amines (Table 7, entries 3-5). In the case of intermo-
lecular MCP hydroamination with aromatic amines, slightly
decreased Nt values are observed with respect to those of
aliphatic amines (Nt ) 0.8 h-1 for entry 2 vs Nt ) 0.25 h-1 for
entry 3). Most likely, this reflects the decreased nucleophilicity
of the aromatic amines. Likewise, electron-rich aromatic amines
(entries 4 and 5) exhibit slightly enhanced Nt values compared
to electron-neutral aromatic amines (entry 3). The greater amine
addition rate can be associated with the increased nucleophilicity
of amine. Selectivity is discussed below.
(69) For the synthesis of MCPs see: Brandi, A.; Goti, A. Chem. ReV. 1998, 98,
589-635.
(70) Reviews: (a) Ohta, T.; Takaya, H. In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon: Oxford, U.K., 1991; Vol. 5, p 1185. (b)
Binger, P.; Buch, H. M. Top. Curr. Chem. 1987, 135, 77-151. (c)
Dzhemilev, U. M.; Khusnutdinov, R. I.; Tolstikov, G. A. J. Organomet.
Chem. 1991, 409, 15-65.
(71) Review: (a) Nakamura, I.; Yamamoto, Y. AdV. Synth. Catal. 2002, 344,
111-129. (b) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49-
92.
(72) (a) Jia, L.; Yang, X.; Seyam, A. M.; Albert, I. D. L.; Fu, P.-F.; Yang, S.;
Marks. T. J. J. Am. Chem. Soc. 1996, 118, 7900-7913. (b) Yang, X.;
Seyam, A. M.; Fu, P.; Marks, T. J. Macromolecules 1994, 27, 4625-4626.
(c) Jensen, T. R.; Marks, T. J. Macromolecules 2003, 36, 1775-1778.
(73) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2001, 4411-4418.
(74) Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.; Kim, Y. J. J. Org. Chem. 1985,
50, 1927-1932.
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A R T I C L E S
Ryu et al.
Table 7. Organolanthanide-Catalyzed Intermolecular Hydroamination of Methylenecyclopropanesa
a Reaction conditions: 5 mol % [Cp′2LnCH(SiMe3)2]; 1.2 equiv of MCP; turnover frequencies (Nt) measured in C6D6. b Determined by 1H NMR spectroscopy
and GC-MS. c Isolated yield of the corresponding free amines in preparative-scale reaction after H2 Pd/C reduction. d Isolated yield of the corresponding free
amines in preparative-scale reaction after the reduction using ZnCl2 and NaBH3CN. e Cp′2LaCH(SiMe3)2 as precatalyst. f Cp′2SmCH(SiMe3)2 as precatalyst.
With regard to regioselectivity and mechanistic pathways, the
MCP olefin insertion into the Ln-N bond can in principle afford
two different regioisomers as a result of either 1,2-addition or
2,1-addition (Scheme 5). Following 1,2-addition of the Ln-N
functionality to the MCP exo methylene (Scheme 5, T4),
ensuing â-alkyl eliminative cyclopropane ring opening of the
Ln-alkyl cyclopropane species 33 affords the Ln-alkyl enam-
ine species 34. Rapid protonolysis of 34 by the amine substrate
gives the enamine intermediate 35, which is tautomerized to
the more stable corresponding imine product. On the other hand,
2,1-addition of the Ln-N bond (Scheme 5, T5) would provide
the Ln-alkyl species 37. Subsequent â-alkyl shift-based ring
opening and followed by protonolysis of the Ln-C bond should
afford the allylamine product 39. Organolanthanide centers
sensitive to steric factors should prefer 1,2-addition (Scheme
5, T4) over 2,1-addition (Scheme 5, T5). Moreover, the C2-
C3 bond of 1,2-addition product 33 can be syn oriented with
respect to the Ln-C bond, while the C3-C4 bond of 2,1-
insertion product 37 is perpendicular to the Ln-C bond. Thus,
the â-alkyl shift of 2,1-addition product 37 is conformationally
disfavored. Importantly, the proposed transition state T4 in
Scheme 5 is in accord with the observed regiochemical outcome
1
in Table 7, entry 1. H NMR spectra of completed, in situ
monitored experiments reveal only resonances attributable to
the 1,2-addition product with no trace of the 2,1-addition
product, allylamine.
It is well-known that â-alkyl elimination processes represent
a major chain termination pathway in lanthanide and cationic
zirconocenium-catalyzed R-olefin polymerization processes.75
In addition, this unique reactivity has been additionally har-
(75) (a) Yang, X.; Stern, C.; Marks, T. J. J. Am. Chem. Soc. 1994, 116, 10015-
10031. (b) Resconi, L.; Piemontesi, F.; Francisco, G.; Abis, L.; Fiorani, T.
J. Am. Chem. Soc. 1992, 114, 1025-1032. (c) Eshuis, J. W.; Tan, Y. Y.;
Teuben, J. H. J. Mol. Catal. 1990, 62, 277-287. (d) Evans, W. J. AdV.
Organomet. Chem. 1985, 24, 131-177. (e) Watson, P. L.; Parshall, G. W.
Acc. Chem. Res. 1985, 18, 51-55.
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Organolanthanide-Catalyzed Hydroamination
A R T I C L E S
Scheme 5. Proposed Catalytic Cycle for Organolanthanide-Catalyzed Intermolecular Methylenecyclopropane Hydroamination
Scheme 6. Proposed Catalytic Pathways for Organolanthanide-Catalyzed Intermolecular Hydroamination of
2-Phenylmethylenecyclopropane
nessed as a ring-opening step in chain propagation and has
provided functionalized polyolefins with backbone exo-meth-
ylene groups.76 The organolanthanide and zirconocenium-
mediated alkyl shift-based ring-opening mechanisms for me-
thylenecycloalkanes have been well-established by 13C labeling
copolymerization experiments of methylenecyclobutane (MCB)
and ethylene (eqs 21 and 22),72a in which the C2-C3/C2-C5
bond is exclusively cleaved (eq 21) rather than the C3-C4/
C4-C5 bond (eq 22).
With regard to hydroamination, an additional intriguing
question arises concerning regioselective ring opening of
unsymmetrical phenylmethylenecyclopropane (PhMCP). In
principle, two different â-alkyl shift pathways are possible in
the intermolecular hydroamination of PhMCP (Scheme 6). C2-
(76) (a) Yang, X.; Jia, L.; Marks, T. J. J. Am. Chem. Soc. 1993, 115, 3392-
3393. (b) Jia, L.; Yang, X.; Yang, S.; Marks, T. J. J. Am. Chem. Soc. 1996,
118, 1547-1548.
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A R T I C L E S
Ryu et al.
Table 8. Ring-Opening Selectivity in the Intermolecular Hydroamination of 2-Phenylmethylenecyclopropane
1
a Determined by GC-MS and H NMR spectroscopy.
C3 bond cleavage would proceed via pathway a. The Ln-alkyl
species 41 generated affords a linear imine product after
protonolysis and ensuing tautomerization. On the other hand,
C2-C4 bond cleavage would provide the homobenzylic lan-
thanide species 44 via pathway b, which would convert rapidly
to branched imine product 46 after protonolysis and tautomer-
ization. Table 8 summarizes the regioselectivites observed in
PhMCP ring opening. In all cases, linear products are observed
as the major product. These results can be understood on the
basis of the same arguments advanced in connection with aryl
directing effects in the regioselectivity of intermolecular vinyl-
arene hydroamination.46,49 Presumably, the lanthanide alkyl
species 40 generated from 1,2-insertion is stabilized by weak
are observed with both Cp′2La- and Cp′2Sm- catalysts, while
aromatic amines exhibit somewhat decreased selectivities
compared to aliphatic amines (entries 3-5). Possibly, the
availability of additional arene π-electron density from aromatic
amine reagents disfavors the preferred conformation (eq 23).
Conclusions
coordination to adjacent arene π-electrons. The arene-lan-
thanide interaction would then favor a syn orientation of Ln-C
and C2-C3 bonds, which would lead to preferential C2-C3
cleavage. Interestingly, in the case of n-propylamine hydroami-
nation (Table 8, entries 1 and 2), excellent regioselectivities
Intermolecular organolanthanide-mediated hydroamination
processes exhibit a broad reaction scope in substrate type,
including alkynes, alkenes, styrenes, butadiene, and methyl-
enecyclopropanes. Complexes such as Me2SiCp′′2NdCH-
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12604 J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003

Organolanthanide-Catalyzed Hydroamination
A R T I C L E S
(SiMe3)2 efficiently and regioselectively catalyze the intermo-
lecular hydroamination of a variety of polarized and nonpolarized
alkenes and alkynes to provide the corresponding amines and
imines with relatively high turnover frequencies. Mechanistic
data implicate turnover-limiting insertion of C-C unsaturation
into Ln-N bonds (involving a highly organized transition state)
with subsequent, rapid Ln-C protonolysis. In addition, the
reaction proceeds with electron-deficient styrenes in good
regioselectivity and yield as well as with electron-rich styrenes.
Remarkably, these processes exhibit stereoelectronically con-
trolled R-substituted effects on regioselectivity. Such transfor-
mations, based on excellent regioselectivities, can be readily
integrated into intramolecular processes following intermolecular
hydroamination to afford highly substituted N-containing com-
plex molecules such as tetrahydroisoquinolines in a single
catalytic cycle. Significantly, preferential intermolecular inser-
tion over intramolecular insertion and sequential tandem bicy-
clization can provide an efficient route to polycyclic alkaloid
skeletons.
Acknowledgment. Financial support by the NSF (Grant No.
CHE-0078998) is gratefully acknowledged.
JA035867M
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