Intermolecular coupling reaction of cyclic amines and alkenes catalyzed by a ruthenium-hydride complex (PCy3)2(CO)RuHCl

Article abstract of DOI:10.1021/om0401206

The ruthenium-hydride complex (PCy₃)₂(CO)-RuHCl (1) was found to be an effective catalyst for the dehydrogenative coupling reaction of cyclic amines and alkenes. The reaction of secondary cyclic amines with unactivated alkenes preferentially gave the C-H bond insertion products in which both C-H and N-H bonds of amines have been selectively activated. In contrast, the reaction of amines with vinylsilane gave the N-silylation products. The catalytically active anionic ruthenium-amido complex was isolated from the reaction mixture, and its structure was established by X-ray crystallography. The preliminary mechanistic studies suggested that both C-H and N-H bond activation steps are mediated by a highly unsaturated ruthenium species.

Full text of DOI:10.1021/om0401206

5392
Organometallics 2004, 23, 5392-5395
Intermolecular Coupling Reaction of Cyclic Amines and
Alkenes Catalyzed by a Ruthenium-Hydride Complex
(PCy3)2(CO)RuHCl
Chae S. Yi* and Sang Young Yun
Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201-1881
Ilia A. Guzei
Molecular Structure Laboratory, Department of Chemistry, University of Wisconsin-Madison,
Madison, Wisconsin 53706-1396
Received September 3, 2004
Summary: The ruthenium-hydride complex (PCy3)2(CO)-
RuHCl (1) was found to be an effective catalyst for the
dehydrogenative coupling reaction of cyclic amines and
alkenes. The reaction of secondary cyclic amines with
unactivated alkenes preferentially gave the C-H bond
insertion products in which both C-H and N-H bonds
of amines have been selectively activated. In contrast,
the reaction of amines with vinylsilane gave the N-
silylation products. The catalytically active anionic
ruthenium-amido complex was isolated from the reaction
mixture, and its structure was established by X-ray
crystallography. The preliminary mechanistic studies
suggested that both C-H and N-H bond activation
steps are mediated by a highly unsaturated ruthenium
species.
reactions of nitrogen heterocycles and alkenes6,7 and sp3
C-H bond insertion and dehydrogenation of tertiary
amines and ethers.8 Selective C-H bond activation of
unprotected amines is especially desired in organic
synthesis due to the prevalent occurrence of nitrogen
compounds in natural products and pharmaceutical
agents. In this article, we wish to report a new catalytic
method for forming substituted cyclic imines from
regioselective dehydrogenative coupling reaction of cy-
clic amines and alkenes by using a well-defined ruthe-
nium-hydride complex, (PCy3)2(CO)RuHCl (1).
We recently reported that complex 1 is an effective
catalyst for both hydrovinylation and silylation reactions
of alkenes and alkynes.9 In an effort to extend its
synthetic utility, we have begun to explore the catalytic
activity of 1 for the coupling reactions of amines and
alkenes. For example, the treatment of pyrrolidine (71
mg, 1.0 mmol) with ethylene (6.0 mmol) in the presence
of 5 mol % of 1 in THF at 80 °C for 24 h gave the C-H
bond insertion product 2a in 86% yield (eq 1). The
Transition metal-catalyzed C-H bond activation re-
actions have been shown to be effective methods for
functionalization of unreactive hydrocarbons.1-5 Since
Murai’s pioneering report on ruthenium-catalyzed re-
gioselective arene-to-alkene coupling reactions,2 a num-
ber of well-defined late transition metal catalysts have
been shown to mediate selective C-H bond activation
of hydrocarbons. The notable recent examples include
direct C-H bond borylation of alkanes by Cp*Rh(arene)
catalysts,3 dehydrogenation of alkanes by Rh and Ir
complexes with P-C-P “pincer” diphosphine ligands,4
and Ru- and Pd-catalyzed oxidative coupling reactions
of arenes and alkenes.5 Recently, late metal complexes
have also been found to catalyze regioselective coupling
organic product 2a was isolated after trap-to-trap
vacuum distillation, and its structure was completely
established by spectroscopic methods. In particular, the
diagnostic imine carbon resonance of 2a was observed
at δ 177.2 by 13C NMR.10 The initial survey of ruthe-
nium catalysts showed that complex 1 was found to
exhibit uniquely high activity among commonly avail-
(1) Recent reviews: (a) Selective Hydrocarbon Activation; Davies,
J. A., Watson, P. L., Greenberg, A., Liebman, J. F., Eds.; VCH: New
York, 1990. (b) Arndtsen, B. A.; Bergman, R. G.; Mobley, T. A.;
Peterson, T. H. Acc. Chem. Res. 1995, 28, 154. (c) Kakiuchi, F.; Murai,
S. Acc. Chem. Res. 2002, 35, 826. (d) Ritleng, V.; Sirlin, C.; Pfeffer, M.
Chem. Rev. 2002, 102, 1731.
(2) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani,
A.; Sonoda, M.; Chatani, N. Nature 1993, 366, 529. (b) Kakiuchi, F.;
Murai, S. In Activation of Unreactive Bonds and Organic Synthesis;
Murai, S., Ed.; Springer: New York, 1999.
(3) Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000,
287, 1995.
(4) (a) Gozin, M.; Weisman, A.; Ben-David, Y.; Milstein, D. Nature
1993, 364, 699. (b) Liu, F.; Pak, E. B.; Singh, B.; Jensen, C. M.;
Goldman, A. S. J. Am. Chem. Soc. 1999, 121, 4086. (c) Kanzelberger,
M.; Singh, B.; Czerw, M.; Krogh-Jespersen, K.; Goldman, A. S. J. Am.
Chem. Soc. 2000, 122, 11017. (d) Gu, X.-Q.; Chen, W.; Morales-Morales,
D.; Jensen, C. M. J. Mol. Catal. (A) 2002, 189, 119.
(5) (a) Weissman, H.; Song, X.; Milstein, D. J. Am. Chem. Soc. 2001,
123, 337. (b) Fujiwara, Y.; Jia, C. Pure Appl. Chem. 2001, 73, 319. (c)
Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P.
C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc.
2002, 124, 1586.
(6) (a) Jun, C.-H.; Hwang, D.-C.; Na, S.-J. Chem. Commun. 1998,
1405. (b) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am.
Chem. Soc. 2003, 125, 1698.
(7) (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2001, 123, 2685. (b) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2002, 124, 13964.
(8) (a) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi,
F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 10935. (b) Ferrando-Miguel,
G.; Coalter, J. N., III; Ge´rard, H.; Huffman, J. C.; Eisenstein, O.;
Caulton, K. G. New J. Chem. 2002, 26, 687. (c) Murakami, M.; Hori,
S. J. Am. Chem. Soc. 2003, 125, 4720. (d) Zhang, X.; Fried, A.; Knapp,
S.; Goldman, A. S. Chem. Commun. 2003, 2060. (e) Lin, Y.; Ma, D.;
Lu, X. Tetrahedron Lett. 1987, 28, 3249.
(9) (a) Yi, C. S.; He, Z.; Lee, D. W.; Rheingold, A. L.; Lam, K.-C.
Organometallics 2000, 19, 2036. (b) Yi, C. S.; He, Z.; Lee, D. W.
Organometallics 2001, 20, 802.
(10) See the Supporting Information for spectroscopic data of these
complexes.
10.1021/om0401206 CCC: $27.50 © 2004 American Chemical Society
Publication on Web 10/05/2004

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Organometallics, Vol. 23, No. 23, 2004 5393
Table 1. Catalytic Coupling Reaction of Cyclic Amines and Alkenes by 1
a Reaction conditions: amine (1.0 mmol); 1 (3-15 mol %); alkene (6-10 mmol); THF (2-5 mL); 16-24 h. b The product yields were
determined by GC. The number in parentheses is the isolated yield from a 1.0 g scale reaction with >95% purity as determined by 1H
NMR.
able ruthenium complexes, such as (PPh3)4RuH2, (PPh3)3-
RuHCl, (p-cymene)RuCl2, [Cp*RuCl2]2, [(PCy3)2(CO)(CH3-
CN)RuH]BF4, and RuCl3‚3H2O.
the reaction was found to be strongly inhibited by added
phosphines. For example, addition of 10 mol % of PCy3
(relative to the amine substrate) to the reaction mixture
of pyrrolidine, ethylene, and 10 mol % of 1 under the
conditions outlined in eq 1 led to <10% of the product
2a after 24 h at 80 °C. The rate constants, kobs ) 5.4 ×
10-2 h-1 without added PCy3 and kobs ) 8.8 × 10-3 h-1
with 10 mol % PCy3, were measured from the first-order
plots of ln[amine] vs time (Supporting Information).
Second, normal isotope effect of kNH/kND ) 1.9 ( 0.1
(average of 3 runs at 80 °C) was observed from the
reactions of C4H8N-H and C4H8N-D with ethylene. In
contrast, no significant carbon isotope effect was ob-
served on formation of 2d and 3d when the R-carbon of
hexamethylenimine at 83% conversion was analyzed by
13C NMR following Singleton’s carbon isotope measure-
ment technique (12C/13C at C(1) ) 0.997, C(2) ) 0.997,
and C(3) ) 1.000 (internal standard); average of 3
runs).12 Furthermore, the reaction of pyrrolidine with
CD2dCD2 gave extensive deuterium incorporation at the
R-methylene position of both 2a and the unreacted
pyrrolidine.
The scope of the coupling reaction was explored to
demonstrate the synthetic utility of the catalyst 1 (Table
1). In general, secondary cyclic amines with unactivated
alkenes produced C-H bond activation products 2
preferentially. A mixture of imine and amine products
2 and 3 was formed for a sterically demanding 3,3-
dimethyl-1-butene (entry 3) and with a seven-membered
cyclic amine (entry 5). Further treatment of isolated
product 3 under the catalytic reaction conditions did not
give 2. In contrast, the reaction with the vinylsilane
CH2dCHSi(OEt)3 exclusively formed the N-silylation
product 4 (entries 4, 6). Acyclic amines gave complex
mixtures of dehydrogenation and disproportionation
products, while no reaction was observed with pip-
eridines. The organic products were isolated by both
trap-to-trap distillation and/or preparatory GC methods
and were satisfactorily characterized by standard spec-
troscopic methods.10 Catalytic examples of forming cyclic
imines are rare; recently, transition and lanthanide
metal catalysts have been utilized to form cyclic imines
from intramolecular hydroamination reactions of alk-
enyl- and alkynylamines.11
In an effort to establish the nature of reactive species,
the reaction mixture of 1 (10 mg, 14 µmol), pyrrolidine
(6 µL, 5 equiv), and ethylene (1.2 mmol) in THF-d8 (0.5
mL) was monitored by NMR. After heating at 80 °C for
2 h, the formation of a new ruthenium-hydride peak at
The following experiments were performed to gain
mechanistic insights into the catalytic reaction. First,
(11) (a) Kondo, T.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc. 2002,
124, 186. (b) Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003,
125, 12584. (c) Ackermann, L. Organometallics 2003, 22, 4367.
(12) (a) Singleton, D. A.; Thomas, A. A. J. Am. Chem. Soc. 1995,
117, 9357. (b) Frantz, D. E.; Singleton, D. A.; Snyder, J. P. J. Am.
Chem. Soc. 1997, 119, 3383.

5394 Organometallics, Vol. 23, No. 23, 2004
Communications
Scheme 1. A Possible Mechanism
Figure 1. ORTEP diagram of 5 drawn with 50% prob-
ability ellipsoids.
1
δ -15.73 (t, JPH ) 20.1 Hz) was detected by H NMR.
The complex was subsequently isolated as a sodium salt
in 75% yield from a preparatory-scale reaction of 1 with
pyrrolidine, ethylene, and NaOH, and its structure was
established as the anionic ruthenium-amido complex
Na[(PCy3)2(CO)(C4H8N)RuHCl] (5) by X-ray crystal-
lography (Figure 1). The molecular structure of 5
showed an octahedral ruthenium center with a trans
geometry between the amido and the metal-hydride
ligands. Even with relatively high uncertainty on bond
distances and angles resulting from a disordered X-ray
diffraction data, the ruthenium-amido nitrogen bond
distance of 5 (Ru-N(1) ) 2.26(7) Å) was significantly
longer than a neutral Ru(II)-amido complex.13 The
isolated complex 5 was found to be an active catalyst
for the coupling reactions of amines and alkenes.14
Much of the reaction mechanism is not clear at this
point. A possible mechanistic path for the catalytic
reaction is outlined in Scheme 1. The previous results
on the formation of a ruthenium-ethyl complex from
reaction 1 with ethylene along with the current phos-
phine inhibition study suggest that the reactive species
is formed via a reversible dissociation of PCy3.15 In light
of recent reports on well-defined 14 e- ruthenium
complexes,16 we suspect that a highly unsaturated
ruthenium species is responsible for both N-H and
C-H bond activation reactions, though the exact struc-
ture of this species is not yet established.17 The elimina-
tion of NaCl and PCy3 from 5 should form a similar
ruthenium-amine/amide complex. The R-CH bond acti-
vation of the coordinated amine and subsequent alkene
insertion would form the dialkyl species 6. Similar R-CH
bond activation of amines by Ru and Os complexes have
been reported.8b The formation of imine product 2 can
be rationalized by invoking the dehydrogenation of
amine and subsequent R-CH imine bond activation/
alkene insertion sequence. In support of this argument,
the formation of ethane was detected by NMR in the
reaction mixture of pyrrolidine and ethylene. To estab-
lish the involvement of cyclic imine species, the coupling
reaction of independently prepared 1-pyrroline (C4H7N)
and ethylene was examined. In this case, polymeric
[(CH2)3CHdN-]n was produced predominantly with a
trace amount of 2a.18 The extensive deuterium incor-
poration on the R-CH2 of 2a suggests that the C-H bond
activation and alkene insertion steps are relatively facile
and reversible, while the observation of a normal isotope
effect of kNH/kND ) 1.9 is consistent with a rate-limiting
N-H bond activation step. An alternate mechanism
involving the formation of a ruthenium-amide complex
from the N-H bond activation would also be consistent
with the observed normal isotope effect and cannot be
ruled out at this time.
The formation of C-H bond insertion product 3
was observed for the cases with sterically demanding
3,3-dimethyl-1-butene and seven-membered hexameth-
yleneimine, and this may have resulted from a competi-
tive reductive elimination from 6 due to a slower rate
of dehydrogenation of amine. In contrast, the N-H
bond activation, alkene insertion, and ethylene elimi-
nation pathway is apparently favored for vinylsilanes
to form the N-silylation product 4. The formation of
ethylene was observed by NMR in the coupling re-
action of pyrrolidine with CH2dCHSi(OEt)3 and 5 mol
% 1 in a sealed NMR tube.19 These results indicate
that both the steric and electronic nature of alkenes
(13) Yi, C. S.; He, Z.; Guzei, I. A. Organometallics 2001, 20, 3641.
(14) Slower rate was observed for 5 (kobs ) 1.9 × 10-2 h-1) compared
to 1 (kobs ) 3.6 × 10-2 h-1) when the reaction described in eq 1 in C6D6
was monitored by 1H NMR. Also, the addition NaOH did not increase
the rate; in fact, addition of an excess amount (>5 equiv to 1) actually
reduced the product yield substantially.
(15) Yi, C. S.; Lee, D. W. Organometallics 1999, 18, 5152.
(16) (a) Huang, D.; Huffman, J. C.; Bollinger, J. C.; Eisenstein, O.;
Caulton, K. G. J. Am. Chem. Soc. 1997, 119, 7398. (b) Baratta, W.;
Herdtweck, E.; Rigo, P. Angew. Chem., Int. Ed. 1999, 38, 1629. (c)
Watson, L. A.; Ozerov, O. V.; Pink, M.; Caulton, K. G. J. Am. Chem.
Soc. 2003, 125, 8426.
(18) Zhang, J.; Gunnoe, T. B. Organometallics 2003, 22, 2291.
(19) Similar ethylene elimination has been commonly observed in
metal-catalyzed silylation reactions. Marciniec, B. In Applied Homo-
geneous Catalysis with Organometallic Compounds; Cornils, B., Her-
rmann, W. A., Eds.; Wiley-VCH: Weinheim, 2002; Vol. 1.
(17) A referee suggested comparing the activity of 1 with Caulton’s
(PCy3)2(H2)RuHCl as a way to infer the possible involvement of a 14
e- complex.8b Indeed, this complex was found to be an equally active
catalyst under the reaction conditions described in eq 1 (84% 2a).

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Organometallics, Vol. 23, No. 23, 2004 5395
are important for the product selectivity. Clearly,
further research is needed to establish the detailed
mechanism.
nature of reactive species for the catalytic reaction are
currently underway.
Acknowledgment. Financial support from the Na-
tional Institute of Health, General Medical Sciences
(R15 GM55987), is gratefully acknowledged.
In summary, the ruthenium-hydride complex 1 was
found to be an effective catalyst for the intermolecular
coupling reaction of cyclic amines and alkenes. The
catalytic reaction achieved a regioselective sp3 C-H
bond activation of unprotected amines to give syntheti-
cally useful cyclic imines and R-substituted amines.
Efforts to establish a detailed mechanism as well as the
Supporting Information Available: Experimental pro-
cedure and crystallographic data of 5 (PDF). This material is
available free of charge via the Internet at http//:pubs.acs.org.
OM0401206