Highly stereoselective intramolecular hydroamination/cyclization of conjugated aminodienes catalyzed by organolanthanides

Article abstract of DOI:10.1021/ja020226x

Efficient intramolecular hydroamination/cyclization of primary and secondary conjugated aminodienes can be effected by using organolanthanide precatalysts of the type Cp-₂LnCH(TMS)₂ (Cp- = η⁵-Me₅C₅; Ln = La, Sm, Y; TMS = SiMe₃) and CGCSmN(TMS)₂ (CGC = Me₂Si(η⁵-Me₄C₅)(^tBuN)). The transformation proceeds cleanly (≥ 90% conversion) at 25-60 °C with good rates and high regioselectivities, and with electronic effects leading to significant rate enhancements. Some features of the reaction parallel monosubstituted aminoalkene hydroamination/cyclization, including rate law (zero order in [aminodiene]), and rate enhancements observed with larger lanthanide ionic radii and/or more open catalyst ligation structures. Good to excellent diastereoselectivity is obtained in the synthesis of 2,5-trans-disubstituted pyrrolidines (80% de) and 2,6-cis-disubstituted piperidines (99% de) with using the corresponding α-methyl aminodiene precursors. Formation of 2-(prop-1-enyl)piperidine with the chiral C1-symmetric precatalyst (S)-Me₂Si(OHF)(CpR*)SmN(TMS)₂ (OHF = η⁵-octahydrofluorenyl; Cp = η⁵-C₅H₃; R* = (-)-menthyl) proceeds with up to 69% ee. Copyright

Full text of DOI:10.1021/ja020226x

Published on Web 06/13/2002
Highly Stereoselective Intramolecular Hydroamination/Cyclization of
Conjugated Aminodienes Catalyzed by Organolanthanides
Sukwon Hong and Tobin J. Marks*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208-3113
Received February 13, 2002
Catalytic N-H addition to C-C multiple bonds is a highly
desirable, atom-economical transformation for the synthesis of
organonitrogen molecules.1,2 Organolanthanides3 are highly efficient
catalysts for the intramolecular hydroamination/cyclization of
aminoalkenes,4,5 aminoalkynes,6 and aminoallenes.7 Nevertheless,
efficient cyclization of amines tethered to 1,2-disubstituted alkenes
has remained elusive8 (presumably for steric reasons4e,f), severely
limiting implementation in stereoselective approaches5 to azacycles
bearing key substituents of naturally occurring alkaloids. However,
from preliminary intermolecular organolanthanide-mediated diene
hydroamination results,9a we envisioned conjugated diene sub-
strates10 as attractive presursors for the synthesis of such azacyclic
targets. Diene substrates are likely to be more reactive because the
conjugated vinyl substituent should stabilize/delocalize the charge
distribution in the insertive transition state (Scheme 1; thermo-
dynamic estimates as described previously.3d,4f,6,7 ). Moreover, the
steric demands of an η3-allyl3 intermediate may enhance ancillary
ligand stereodirecting effects for diastereo- and enantioselective
pathways to substituted pyrrolidines and piperidines. Herein we
report the organolanthanide-catalyzed hydroamination/cyclization
of conjugated aminodienes11 as examples of efficient hydroami-
nation/cyclization of amines tethered to 1,2-disubstituted alkenes
and initial observations on scope, selectivity, and mechanism.9b
R* ) (-)-menthyl)13 precatalysts is clean and general in scope
(Table 1).14 Thus, 2-substituted pyrrolidines (entries 1-5, 8-12)
and piperidines (entries 6, 7) are formed via 5-exo and 6-exo
cyclizations, respectively. Products a/b are obtained as major
products (entries 1-8) for terminal dienes, however, products c/d
predominate when 1,4-disubstituted substrates are employed (entries
9-12).15 High conversions and reasonably rapid turnover frequen-
cies are observed at 25 or 60 °C. Note that the predicted rate
enhancement vs 4-pentenamine and 5-hexenamine is operative
despite increased substrate steric encumbrance.16 Furthermore, Nt
varies with terminal substituent in the order Me < H < Ph (Nt )
0.02, 0.79, 2.3 h-1, respectively; entries 10, 2, 12), in accord with
proposed transition state electronic demands (Scheme 1). Catalyst
structural effects similar to those in monosubstituted alkene
hydroamination are also operative. Nt increases with increasing
metal ionic radius4f,17 (La > Sm > Y; entries 1-3, entries 9-10,
entries 11-12) and approximately with more open ligation (OHF*,
Table 1. Results for Organolanthanide-Catalyzed Hydroamination/
Cyclization of Conjugated Aminodienes
Scheme 1. Proposed Catalytic Cycle for
Organolanthanide-Mediated Hydroamination of Conjugated
Aminodienes
a Determined by 1H NMR. b Isolated yield (entry 8) or that of Cbz
carbamate (entry 7). c Other Ri ) H. d Determined by 1H NMR and/or GC-
MS of Boc derivatives. e Turnover frequencies measured in C6D6 with 3-11
mol % precatalyst. f OHF* ) (S)-Me2Si(η5-octahydrofluorenyl)(CpR*), R*
) (-)-menthyl. g Determined by the GC-MS ratio of corresponding
hydrogenated Boc derivatives. h Cis:trans ) 178:1; alkene isomer ratio (a:
b:c) ) 94:1:5.
Anaerobic cyclization of primary and secondary aminodienes
mediated by Cp′2LnCH(TMS)2 (Cp′ ) η5-Me5C5),12 CGCSmN-
(TMS)2 (CGC ) Me2Si(η5-Me4C5)(tBuN)),4c or (S)-Me2Si(OHF)-
(CpR*)SmN(TMS)2 (OHF ) η5-octahydrofluorenyl; Cp ) η5-C5H3;
* Corresponding author. E-mail: t-marks@northwestern.edu.
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J. AM. CHEM. SOC. 2002, 124, 7886-7887
10.1021/ja020226x CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
CGC . Cp′2; entries 5, 4, and 2). Preliminary kinetic studies11
reveal linear dependence of reaction time on [substrate] up to ∼75%
conversion, consistent with zero-order kinetic dependence on
[substrate] (turnover-limiting intramolecular alkene insertion).
Good to excellent diastereoselectivities are observed in formation
of a 2,5-trans-disubstituted pyrrolidine (entries 13,14) and a 2,6-
cis-disubstituted piperidine (entries 15, 16) from the corresponding
methyl-substituted dienes.18 Note that entry 15 demonstrates a
concise, efficient synthesis of (()-pinidine19 with excellent stereo-
controls for both 2,6-cis substitution (cis:trans ) 178:1) and trans-
alkene geometry (14a:b:c ) 94:1:5). The high selectivities can be
rationalized by assuming chairlike transition states in which methyl
and diene units occupy thermodynamically more stable equatorial
positions (Figure 1). Preliminary studies of enantioselective cy-
and Mr. R. L. Paddock for help with chiral HPLC measurements,
and Prof. F. E. McDonald and Dr. M. R. Douglass for helpful
suggestions.
Supporting Information Available: Detailed synthetic procedures
and analytical data for new compounds and kinetic plots (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For recent reviews of catalytic hydroamination, see: Mu¨ller, T. E.; Beller,
M. Chem. ReV. 1998, 98, 675-703.
(2) For recent examples of hydroamination catalyzed by transition metals,
see: (a) Johnson, J. S.; Bergman, R. G. J. Am. Chem. Soc. 2001, 123,
2923-2924. (b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000,
122, 9546-9547. (c) Haak, E.; Siebeneicher, H.; Doye, S. Org. Lett. 2000,
2, 1935-1937. (d) Vasen, D.; Salzer, A.; Gerhards, F.; Gais, H.-J.;
Stu¨rmer, R.; Bieler, N. H.; Togni, A. Organometallics 2000, 19, 539-
546. (e) Mu¨ller, T. E.; Grosche, M.; Herdtweck, E.; Pleier, A.-K.; Walter,
E.; Yan, Y.-K. Organometallics 2000, 19, 170-183. (f) Burling, S.; Field,
L. D.; Messerle, B. A. Organometallics 2000, 19, 87-90.
(3) For relevant organolanthanide discussions, see: (a) Topics in Organo-
metallic Chemistry; Kobayashi, S., Ed.; Springer: Berlin, Germany, 1999;
Vol. 2. (b) Molander, G. A. Chemtracts: Org. Chem. 1998, 11, 237-
263. (c) Edelmann, F. T. Top. Curr. Chem. 1996, 179, 247-276. (d) Nolan,
S. P.; Stern, D.; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 7844-7853.
(4) (a) Molander, G. A.; Dowdy, E. D.; Pack, S. K. J. Org. Chem. 2001, 66,
4344-4347. (b) Kim, Y. K.; Livinghouse, T.; Bercaw, J. E. Tetrahedron
Lett. 2001, 42, 2933-2935. (c) Tian, S.; Arredondo, V. M.; Stern, C. L.;
Marks, T. J. Organometallics 1999, 18, 2568-2570. (d) Gilbert, A. T.;
Davis, B. L.; Emge, T. J.; Broene, R. D. Organometallics 1999, 18, 2125-
2132. (e) Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1998, 63, 8983-
8988. (f) Gagne´, M. R.; Stern, C. L.; Marks, T. J. J. Am Chem. Soc. 1992,
114, 275-294.
Figure 1. Plausible transition state for diastereoselective aminodiene
hydroamination/cyclization.
(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) Giardello, M. A.;
Conticello, V. P.; Brard, L.; Sabat, M.; Rheingold, A. L.; Stern, C. L.;
Marks, T. J. J. Am. Chem. Soc. 1994, 116, 10212-10240.
clizations reveal that 3f 4a/b conversion catalyzed by C1-
symmetric (S)-Me2Si(OHF)(CpR*)SmN(TMS)2 proceeds with up
to 69% ee (Table 2, entries 2-4) while analogous 1 f 2a/b
cyclization proceeds with 23% ee (Table 2, entry 1). In contrast,
previous intramolecular aminomonoalkene hydroamination/cycliza-
tions to such piperidines exhibit far lower Nt values and
enantioselectivities;5a the present results constitute the best com-
bination of reactivity and selectivity to date.
(6) (a) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757-1771. (b)
Bu¨rgstein, M. R.; Berberich, H.; Roesky, P. W. Organometallics 1998,
17, 1452-1454. (c) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118,
9295-9306.
(7) (a) Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am.
Chem. Soc. 1999, 121, 3633-3639. (b) Arredondo, V. M.; McDonald, F.
E.; Marks, T. J. Organometallics 1999, 18, 1949-1960. (c) Arredondo,
V. M.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 4871-
4872.
(8) Elevated reaction temperatures, large metal ionic radii/high coordinative
unsaturation, and gem-dimethyl substrate substitution are necessary for
reasonable Nt values in 1,2-disubstituted alkene hydroaminations: Ryu,
J.-S.; Marks, T. J.; McDonald, F. E. Org. Lett. 2001, 3, 3091-3094.
(9) (a) Li, Y.; Marks, T. J. Organometallics 1996, 15, 3770-3772. (b) Hong,
S.; Marks, T. J. Abstracts of Papers; communicated in part at the 221st
National Meeting of the American Chemical Society, San Diego, CA,
April 2001; American Chemical Society: Washington, DC, 2001; abstract
INOR 613.
Table 2. Enantioselective Cyclization of Aminodienesa
entry
substrate
product (ratio)
solvent
temp (°C)
% eeb (config.)c
1
2
3
4
1
3
3
3
2a/b (93:7)
4a/b (97:3)
4a/b (96:4)
4a/b (95:5)
C6D6
C6D6
C6D12
C6D12
25
25
25
0
23
63 (R)
66 (R)
69 (R)
(10) Pd-catalyzed intermolecular hydroamination of dienes by arylamines:
Lo¨ber, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
4366-4367.
a Conditions: 7 mol % (entries 1, 2, 3) or 20 mol % (entry 4) of
(OHF*)SmN(TMS)2 catalyst, ∼0.6 mL of solvent. b For the major isomer,
determined by chiral HPLC analysis. Measured ee values vary only weakly
with conversion. c Determined by optical rotation of the HCl salt of
hydrogenated product. See Supporting Information.
(11) See Supporting Information for full experimental details.
(12) Jeske, G.; Lauke, H.; Mauermann, H.; Swepston, P. N.; Schumann, H.;
Marks, T. J. J. Am. Chem. Soc. 1985, 107, 8091-8103.
(13) Douglass, M. R.; Ogasawara, M.; Hong, S.; Metz, M. V.; Marks, T. J.
Organometallics 2002, 21, 283-292.
(14) For discussion of functional group tolerance in organolanthanide catalysis,
see ref 3b.
(15) For cyclization of dienes 7 and 9, the product distribution is time-
dependent, ultimately favoring thermodynamic products. For conversion
9 f 10, initial formation of 10a and subsequent isomerization to 10c is
observed in situ by 1H NMR. Presumably, the doubly activated benzylic
C-H functionality in 10a is sufficiently acidic to facilitate isomerization.
(16) (a) For example, when Cp′2LaCH(TMS)2 is used as a precatalyst, Nt for
4-pentenamine cyclization is 13 h-1 (25 °C) and Nt for 5-hexenamine
cyclization is 5 h-1 (60 °C)4f vs entries 1 and 6 in Table 1. (b) When
(S)-Me2Si(OHF)(CpR*)SmN(TMS)2 is used as precatalyst, Nt for 4-pen-
tenamine cyclization is 2.6 h-1 at 25 °C.13 Compare to Table 1, entry 5.
(17) Representative eight-coordinate effective ionic radii (Å): La(III), 1.160;
Nd(III), 1.109; Sm(III), 1.079; Y(III), 1.019; Yb(III), 0.985; Lu(III), 0.977.
See: Shannon, R. D. Acta Crystallogr., Sect. A 1976, A32, 751-767.
(18) Relative stereochemistry confirmed by NOESY experiments and deriva-
tization.
In conclusion, we have demonstrated that efficient organolan-
thanide-catalyzed intramolecular hydroamination/cyclization of
amines tethered to 1,2-disubstituted alkenes is achieved by using
readily accessible conjugated aminodienes. The results include rate
enhancements due to electronic effects as well as good regio- and
diastereoselectivity. That aminodienes offer general and efficient
substrates for enantioselective hydroamination/cyclization routes to
2-substituted azacycles motivates current work with other catalysts
and conjugated substrates, and application of this methodology to
alkaloid synthesis.
(19) Kirihara, M.; Nishio, T.; Yokoyama, S.; Kakuda, H.; Momose, T.
Tetrahedron 1999, 55, 2911-2926 and references therein.
Acknowledgment. We thank NSF (CHE-0078998) for support,
Dr. Y. Wu for help with NOESY experiments, Prof. S. T. Nguyen
JA020226X
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