Organolanthanide-catalyzed intramolecular hydroamination/ cyclization of amines tethered to 1,2-disubstituted alkenes

Article abstract of DOI:10.1021/ol010129t

(equation presented) This contribution reports the organolanthanide-catalyzed intramolecular hydroamination/cyclization of amines tethered to 1,2-disubstituted alkenes to afford the corresponding mono-and disubstituted pyrrolidines and piperidines by usin

Full text of DOI:10.1021/ol010129t

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3091-3094
Organolanthanide-Catalyzed
Intramolecular Hydroamination/
Cyclization of Amines Tethered to
1,2-Disubstituted Alkenes
Jae-Sang Ryu,† Tobin J. Marks,* and Frank E. McDonald*
,†
,‡
Departments of Chemistry, Northwestern UniVersity, 2145 Sheridan Road,
EVanston, Illinois 60208, and Emory UniVersity, 1515 Pierce DriVe,
Atlanta, Georgia 30322
tjmarks@casbah.acns.nwu.edu
Received June 11, 2001
ABSTRACT
This contribution reports the organolanthanide-catalyzed intramolecular hydroamination/cyclization of amines tethered to 1,2-disubstituted
alkenes to afford the corresponding mono- and disubstituted pyrrolidines and piperidines by using coordinatively unsaturated complexes of
t
the type (η5-Me C ) LnCH(TMS)2 (Ln ) La, Sm), [Me Si(η5-Me C ) ]NdCH(TMS)2, [Et2Si(η5-Me C )(η5-C H )]NdCH(TMS)2, and [Me Si(η5-Me C )( BuN)]-
5
5 2
2
4
5 2
4
5
5
4
2
4 5
LnE(TMS)2 (Ln ) Sm, Y, Yb, Lu; E ) N, CH) as precatalysts. [Me2Si(η5-Me4C )( BuN)]LnE(TMS)2 mediates intramolecular hydroamination/
t
5
cyclization of sterically demanding amino-olefins to afford disubstituted pyrrolidines in high diastereoselectivity (trans/cis ) 16/1) and in good
to excellent yield.
In terms of atom economy, catalytic N-H bond addition to
unactivated C-C multiple bonds1-3 is potentially one of the
most efficient and elegant processes for construction of
naturally occurring alkaloid skeletons. Over the past decade,
catalytic regio-/diastereo-/enantioselective intramolecular cy-
clohydroamination catalyzed by trivalent lanthanocene com-
plexes4 has been extensively investigated. Major advances
include cycloaminations of aminoalkenes,5 aminoalkynes,6
and aminoallenes,7 tandem bicyclizations of aminodienes,
aminodiynes, and aminoenynes,8 and recent application to
the stereoselective synthesis of the bicyclic alkaloid, (+)-
xenovenine.9 Organolanthanide-mediated intermolecular hy-
droamination has also been demonstrated.10 The efficiency
of these catalytic reactions is remarkable with regard to high
turnover frequencies5,6 (Nt ) 5-140 h-1 for terminal
aminoalkenes; 4-7600 h-1 for aminoalkynes), versatility of
alkylation pattern and ring size,5-8 and high stereoselectiv-
ity.5-11 Despite these attractive features, organolanthanide-
(2) For hydroamination mediated by late transition metals, see: (a)
Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 112, 9546-9547.
(b) Mu¨ller, T. E.; Pleier, A.-K. J. Chem. Soc., Dalton Trans. 1999, 583-
587. (c) Al-Masum, M.; Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1997,
38, 6071-6074. (d) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.;
Peterson, K. P. J. Org. Chem. 1996, 61, 3584-3585. (e) Besson, L.; Gore´,
J.; Cazes, B. Tetrahedron Lett. 1995, 36, 3857-3860. (f) Seligson, A. L.;
Trogler, W. C. Organometallics 1993, 12, 744-751. (g) Tamaru, Y.; Hojo,
M.; Higashimura, H.; Yoshida, Z.-I. J. Am. Chem. Soc. 1988, 110, 3994-
4002. (h) Armbruster, R. W.; Morgan, M. M.; Schmidt, J. L.; Lau, C. M.;
Riley, R. M.; Zabrowski, D. L.; Dieck, H. A. Organometallics 1986, 5,
234-237. (i) Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc. 1982,
104, 2444-2451.
* Additional corresponding author email: fmcdona@emory.edu.
† Northwestern University.
‡ Emory University.
(1) For reviews of catalytic amine addition to C-C multiple bonds, see:
(a) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998. 98, 675-703 and references
therein. (b) Roundhill, D. M. Catal. Today 1997, 37, 155-165. (c) Hegedus,
L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113-1126.
10.1021/ol010129t CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/07/2001

catalyzed cyclohydroamination of amines tethered to more
encumbered alkenes (e.g., 1,2-disubstituted alkenes) has
remained elusive7a,12 (cf. eq 1).
Cyclizations of amines tethered to 1,2-disubstituted alkenes
are of fundamental importance for the construction of
heterocyclic systems bearing key substituents present in
naturally occurring alkaloids. Although cyclohydroamination
of aminoalkynes and aminoallenes can introduce a variety
of longer chain alkyl substituents onto product pyrrolidine
and piperidine skeletons, the synthesis of these substrates is
not necessarily straightforward. Furthermore, additional
reductive transformations of the resulting imine or alkene
products are required to obtain saturated targets. We now
report that the use of more coordinatively unsaturated and
thermally robust organolanthanide complexes combined with
higher reaction temperatures allows extension of aminoalkene
cyclohydroaminations to 1,2-disubstituted alkenes.13
Facile organolanthanide-catalyzed cyclohydroamination
demonstrates that insertion of C-C multiple bonds into
Ln-N bonds via a four-centered transition state (T1, Figure
1) can be efficaciously coupled to rapid protonolysis of the
resulting Ln-C bonds11 (i.e., 3 f 4; Figure 1). The inherent
limitation in 1,2-disubstituted alkene insertion is reasonably
attributed to severe nonbonded repulsions and possible charge
separation imbalance in the reasonably well-characterized
transition state11 (T1, Figure 1), both deriving from the
sterically demanding, electron-donating alkyl substitution.
The steric sensitivity of the olefin insertion step doubtless
reflects subtle changes in the catalyst coordination environ-
(3) For hydroaminations mediated by early transition metals, see: (a)
Kim, Y. K.; Livinghouse, T.; Bercaw, J. E. Tetrahedron Lett. 2001, 42,
2933-2935. (b) Haak, E.; Siebeneicher, H.; Doye, S. Org. Lett. 2000, 2,
1935-1937. (c) Molander, G. A. Chemtracts: Org. Chem. 1998, 11, 237-
263. (d) McGrane, P. L.; Livinghouse, T. J. Am. Chem. Soc. 1993, 115,
11485-11489. (e) Baranger, A. M.; Walsh, P. J.; Bergman, R. G. J. Am.
Chem. Soc. 1993, 115, 2753-2763. (f) Walsh, P. J.; Hollander, F. J.;
Bergman, R. G. Organometallics 1993, 12, 3705-3723. (g) McGrane, P.
L.; Jensen, M.; Livinghouse, T. J. Am. Chem. Soc. 1992, 114, 5459-5460.
(4) For organolanthanide reviews, see: (a) Deacon, G. B.; Shen, Q. J.
Organomet. Chem. 1996, 506, 1-17. (b) Schumann, H.; Meese-Marktschef-
fel, J. A.; Esser, L. Chem. ReV. 1995, 95, 865-986. (c) Edelmann, F. T.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2466-2488.
(5) (a) Giardello, M. A.; Conticello, V. P.; Brard, L.; Gagne´, M. R.;
Marks, T. J. J. Am. Chem. Soc. 1994, 116, 10241-10254. (b) Gagne´, M.
R.; Nolan, S. P.; Marks, T. J. Organometallics 1990, 9, 1716-1718. (c)
Gagne´, M. R.; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 4108-4109.
(6) (a) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 9295-9306.
(b) Li, Y.; Fu, P.-F.; Marks, T. J. Organometallics 1994, 13, 439-440.
(7) (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.
Figure 1. Proposed catalytic cycle for organolanthanide-catalyzed
cyclohydroamination of aminoalkenes.
ment, and therefore lanthanide ions of maximum ionic radius
and more open ancillary ligation should in principle reduce
congestion.11 Previous kinetic studies of 2,2-dimethyl-4-
pentene-1-amine cyclohydroamination (A, eq 2) revealed a
(8) (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.
(9) Arredondo, V. A.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am.
Chem. Soc. 1999, 121, 3633-3639.
(10) Li, Y.; Marks, T. J. Organometallics 1996, 15, 3370-3372.
(11) Gagne´, M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1992,
114, 275-294.
significant rate dependence on lanthanide ionic radius (Nt
) 95 s-1 (25 °C) for La3+ vs Nt < 1 s-1 (80 °C) for Lu3+)11
and enhanced activity using more open organolanthanide
centers (e.g., Nt ) 181 h-1 (25 °C) for (CGC)SmN(TMS)2
(5a) vs Nt ) 48 h-1 (80 °C) for Cp′2SmCH(TMS)2 (8b)).14b
(12) Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1998, 63, 8983-
8988.
(13) Ryu, J.-S.; Marks, T. J.; McDonald, F. E. Presented in part at the
221st National Meeting of the American Chemical Society, San Diego, CA,
April 1-5, 2001; Abstract ORGN 265.
3092
Org. Lett., Vol. 3, No. 20, 2001

(Table 1).15 At 2-10 mol %16 catalyst loadings and at 120-
130 °C, the anaerobic, anhydrous, NMR-scale reaction of
2,2-dimethyl-4-hexen-1-amine (9) proceeds rapidly and
cleanly to cyclized product (Table 1, entry 1). For substrates
not bearing an alkyl substituent at the C1 position (Table 1,
entries 1-3), cyclization mediated by both the Cp′2La system
8a and the (CGC)Ln system 5a-d affords the corresponding
cyclized products. Although Cp′2La complex 8a serves as a
generally effective catalyst for less sterically demanding
substrates such as 9, 11, and 13, significant depression of
the conversion in Cp′2La-catalyzed cyclization is observed
for an aminoalkene with a methyl substituent at the C1
position (17, entry 5). Apparently the C1 methyl substituent
and the alkene methyl substituent incur significant repulsive
steric interactions with the Cp′ methyl groups in the transition
state (e.g., B). However, efficient reaction rates and good
Table 1. Results for Organolanthanide-Catalyzed
Intramolecular Cyclohydroamination of the Amines Tethered to
1,2-Disubstituted Alkenesa
stereoselectivities are observed in cyclohydroaminations of
17 with catalysts offering a more open coordination environ-
ment, such as (CGC)Ln catalysts 5a, 5b, and 5d. (Although
correlations of activity and ionic radius are not as clear-cut
as in the case of less hindered R-olefinic systems).11,14b
Cyclohydroamination of substrate 17 proceeds with excellent
trans diastereoselectivity, consistent with an envelope-like
transition state (Figure 2). Among several possible conform-
a All reactions conducted in C6D6 or C7D8. b Determined by 1H NMR
spectroscopy and GC-MS. c Isolated yield of the corresponding HCl salt
in preparative-scale reaction. d Isolated yield in NMR-scale reaction.
1
e Similar trans:cis ratio observed by H NMR spectroscopy.
To this end, we investigated lanthanocenes with relatively
large ionic radii (La3+ ) 1.160 Å > Sm3+ ) 1.079 Å) and
lanthanide complexes having more open and rigid ligation
spheres (ansa-Me2SiCp′′Cp, ansa-Me2SiCp′′2, and CGC )
[Me2Si(η5-Me4C5)(tBuN)], Figure 1),14a using elevated reac-
tion temperatures and relatively high catalyst loadings (2-
10 mol %).
Figure 2. Plausible cyclohydroamination intermediates and path-
way yielding trans-2-ethyl-5-methyl-pyrrolidine (14).
The organolanthanide-catalyzed cyclohydroamination of
a representative series of aminoalkene substrates was studied
using a selected grouping of the aforementioned catalysts
ers, conformer II offers minimal 1,3-diaxial interactions,
consistent with the observed diastereoselectivity.17
NMR monitoring of cyclohydroaminations that require
relatively long reaction times occasionally reveals declining
turnover frequencies beyond one half-life. This effect is
reasonably attributed to competitive inhibition by the Lewis
basic product11 and/or noncompetitive inactivation via ther-
(14) (a) Crystal structure data show CGC complex Cp(c)-M-N angles
(Cp(c) ) ring centroid) to be 25-28° smaller than Cp(c)-M-Cp(c) angles
in the corresponding biscyclopentadienyl lanthanocenes. (b) Tian, S.;
Arredondo, V. A.; Stern, C. L.; Marks, T. J. Organometallics 1999, 18,
2568-2570.
Org. Lett., Vol. 3, No. 20, 2001
3093

mal decomposition of the catalytically active L2Ln-
NHR(NH2R)n species. To investigate the latter question
further, the intrinsic thermolytic stability of several organo-
lanthanide precatalysts was scrutinized in C6D12 solution. The
concentration of diamagnetic precatalyst vs. time profiles
depicted in Figure 3 illustrate approximately zero-order
tion profile of the Cp′2La-hydrocarbyl precursor suggests an
intramolecular thermolytic pathway, likely involving ring
metalation and η6-Me4C5CH2 formation.19 In the presence
of amine substrates, the Cp′2La system exhibits catalytic
activity at 120 °C for several days with slowly declining
1
η5-Cp′ signals in the H NMR. This result implies that
catalytically active Cp′2La(NHR)(NH2R)n species are more
thermally stable than the hydrocarbyl precursor and/or that
η6-Me4C5CH2 species readily revert to active catalysts upon
protonolysis (eq 3).19d,19e
(Me5C5)La(η6-Me4C5CH2) nNH R8
2
(Me5C5)2La-NHR(NH2R)n (3)
In summary, limitations in the elusive addition of lan-
thanide-N bonds to 1,2-disubstituted alkenes have been
overcome, and substrate generality for future synthetic
applications has been demonstrated. Lanthanocenes such as
(CGC)LnE(TMS)2 (Ln ) Sm, Y, Lu; E ) CH, or N)
complexes with more open coordination spheres serve as
effective precatalysts for sterically-demanding olefinic
substrates.
Acknowledgment. Financial support by the NSF (CHE-
0078998) is gratefully acknowledged. We thank Dr. S. Tian
for [Me2Si(η5-Me4C5)(tBuN)]LnE(TMS)2 (Ln ) Sm, Y, Yb,
Lu; E ) N, CH) samples.
Figure 3. Thermolysis rate data for organolanthanide precatalysts
in sealed tubes at 120 °C: (a) A 16.8 mM Cp′2LaCH(TMS)2
solution in C6D12 with Cp2Fe as an internal calibration standard
(O). (b)18 A 10.7 mM (CGC)YN(TMS)2 solution in C6D12 with
Cp2Fe as an internal calibration standard (b).
Supporting Information Available: Detailed synthetic
procedures and analytical data for the compounds 9-18. This
material is available free of charge via the Internet at
http://pubs.acs.org.
behavior in [precatalyst]. The thermal decomposition rate
of (CGC)YN(TMS)2 is clearly slow at 120 °C, while pre-
catalyst Cp′2LaCH(TMS)2 decomposes rapidly. The diminu-
tion of precatalyst Cp′ resonances at δ 2.015 and 1.972 ppm
and the quantitative evolution of CH2(TMS)2 resonances at
OL010129T
(18) Similar kinetic behavior is observed in C7D8 without the ferrocene
internal standard.
1
δ 0.030 and -0.268 ppm are observed by H NMR. The
zero-order kinetic behavior and relatively rapid decomposi-
(19) (a) Riley, P. N.; Parker, J. R.; Fanwick, P. E.; Rothwell, I. P.
Organometallics 1999, 18, 3579-3583. (b) Sun, Y.; Spence, R. E. v. H.;
Piers, W. E.; Parvez, M.; Yap, G. P. A. J. Am. Chem. Soc. 1997, 119,
5132-5143. (c) Brunner, H.; Wachter, J. Organometallics 1996, 15, 1327-
1330. (d) Booij, M.; Meetsma, A.; Teuben, J. H. Organometallics 1991,
10, 3246-3252. (e) Schock, L. E.; Marks, T. J. J. Am. Chem. Soc. 1988,
110, 7701-7715. (f) Schock, L. E.; Brock, C. P.; Marks, T. J. Organo-
metallics 1987, 6, 1219-1226. (g) Bulls, R. A.; Schaefer, W. P.; Serfas,
M.; Bercaw, J. E. Organometallics 1987, 6, 1219-1226. (h) McDade, C.;
Green, J. C.; Bercaw, J. E. Organometallics 1982, 1, 1629-1634.
(15) Reactions were conducted in Teflon-valve-sealed NMR tubes and
1
monitored by H NMR (see Supporting Information for details).
(16) In general, <1 mol % of precatalyst suffices for practical reaction
rates in the case of aminoalkynes, aminoallenes, and amines tethered to
terminal alkenes.5-11
1
(17) The trans:cis ratio was determined by H NMR spectroscopy, and
the major isomer confirmed by 2-D NOESY experiments.
3094
Org. Lett., Vol. 3, No. 20, 2001