Mechanistic studies of ruthenium-catalyzed anti-Markovnikov hydroamination of vinylarenes: Intermediates and evidence for catalysis through π-arene complexes

Article abstract of DOI:10.1021/ja0506410

Studies are described that reveal the steps of the anti-Markovnikov hydroamination of vinylarenes with alkylamines catalyzed by Ru(COD)(2-methylallyl)₂, bis(diphenylphosphino)pentane, and TfOH. Treatment of the catalyst components with an exces

Full text of DOI:10.1021/ja0506410

Published on Web 04/02/2005
Mechanistic Studies of Ruthenium-Catalyzed Anti-Markovnikov
Hydroamination of Vinylarenes: Intermediates and Evidence for Catalysis
through π-Arene Complexes
Jun Takaya and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107
Received January 31, 2005; E-mail: John.Hartwig@yale.edu
Scheme 1
Catalytic hydroamination of alkenes is an addition process that
allows control of regiochemistry and stereochemistry.1 Several
mechanisms for hydroamination of alkenes have been elucidated.
One pathway occurs by activation of alkenes toward nucleophilic
attack;2 two additional pathways include N-H activation;3 a third
pathway occurs by imido complexes that undergo [2 + 2] reactions
with olefins,4 and a fourth pathway includes nucleophilic attack of
an amine on an (η3-arylethyl)Pd complex.5
Seeming unrelated to hydroamination at first, the stoichiometric
Scheme 2
reactivity of π-arene ligands has been widely investigated as a
means to elaborate aromatic structures.6 Although catalytic versions
of these transformations of π-arene ligands would be highly
desirable, only one catalytic process involving modification of an
arene ligand was cited in a recent review describing π-arene
complexes as catalysts.7
We report evidence that catalytic hydroamination and the
reactions of π-arene complexes converge at our anti-Markovnikov
addition of alkylamines to vinylarenes catalyzed by the combination
of Ru(COD)(2-methylallyl)2, DPPPent,8 and TfOH (eq 1).9 We
show that these catalyst precursors generate an η6-styrene complex,
and we provide evidence that the anti-Markovnikov hydroamination
catalyzed by this ruthenium system occurs by attack of amine on
this η6-styrene complex and exchange of π-arene ligands.
a Yield by GC. bRu(COD)(2-methylallyl)2 (5 mol %), DPPPent (7 mol
%), TfOH (10 mol %).
Scheme 3
(2.253(3)-2.289(3) Å) bond lengths are similar to those of previous
Ru-pincer and Ru-arene complexes.11 The dihedral angle between
the plane of the olefin and of the arene is only 3.7°, implying that
To deduce the mechanism of the hydroamination of vinylarenes
catalyzed by Ru(COD)(2-methylallyl)2, DPPPent, and TfOH, we
studied the products generated by various combinations of the
catalyst components, styrene, and morpholine. A mixture of Ru-
(COD)(2-methylallyl)2, DPPPent, and TfOH and an excess of
styrene in THF at 80 °C generated the new (η6-styrene)ruthenium
complex 1a in Scheme 1. This complex was isolated in 67% yield
as a pale yellow, crystalline solid. An analogous (η6-cymene)-
ruthenium complex 2 was prepared in 64% yield by the same
reaction with cymene instead of styrene. A combination of
protonolysis of the allyl groups, replacement of COD by the
DPPPent ligand, metalation of the central carbon of the pentane
backbone of the DPPPent ligand, and coordination of the arene to
the PCP-ruthenium fragment generates 1a and 2.
the olefin remains conjugated with the arene.
Isolated 1a is competent as a catalyst for the hydroamination.
The reaction of styrene with morpholine in the presence of 5 mol
% of 1a in dioxane at 100 °C occurred slightly faster than the
reaction catalyzed by Ru(COD)(2-methylallyl)2, DPPPent, and
TfOH and afforded the same anti-Markovnikov adduct in high yield
(Scheme 2). Cymene complex 2 also catalyzed the hydroamination
reaction on a comparable time scale.
Complex 1a reacted readily with morpholine. This reaction of
1a with 20 equiv of morpholine in a mixture of dioxane and NMP
formed the η6-morpholinoethylarene complex 3a at room temper-
ature by nucleophilic attack at the terminus of the vinylarene
(Scheme 3). Clearly, the fast rate of attack on the styrene results
from the activation of the vinylarene by coordination to the metal.
Complex 3a was characterized by conventional NMR spectroscopic
methods and by X-ray diffraction (Figure S2). The structure of the
core of 3a is nearly superimposable with the core of the styrene
complex 1a.
Complexes 1a and 2 were characterized by 1H, 13C, and
multinuclear 2D NMR spectroscopy, and 1a was characterized by
X-ray diffraction. The aromatic protons of 1a resonated at 5.3-
6.8 ppm, which is typical of transition-metal-arene complexes. The
methine proton of the ligand backbone was unusually downfield
(4.8 ppm), presumably from deshielding by the styrene ring.10
The structure of 1a by X-ray diffraction (Figure S1) reveals the
cyclometalated structure of the PCP ligand and the presence of the
η6-vinylarene ligand. The Ru-C(23) (2.198(3) Å) and Ru-styrene
The most likely mechanism for the formation of 3a is direct
nucleophilic attack of morpholine on the terminus of the styrene.12
Such a nucleophilic addition would occur through a zwitterionic
intermediate in which the generated anion could be stabilized by
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J. AM. CHEM. SOC. 2005, 127, 5756-5757
10.1021/ja0506410 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
Scheme 6
Scheme 5
DPPPent. Consistent with our hypotheses, the reaction of styrene
with morpholine was faster when catalyzed by the complex
generated from a DPPPent analogue containing 3,5-dimethoxyphe-
nyl groups. This reaction in THF at 80 °C was roughly 3.5 times
faster with this catalyst 1b than with the catalyst 1a.
In summary, our mechanistic data strongly suggest that the
ruthenium-catalyzed anti-Markovnikov hydroamination of arenes
occurs by a new mechanism involving a rare example of catalytic
chemistry through π-arene complexes. These findings suggest that
further catalytic processes can be developed through Michael-type
additions of nucleophiles other than amines to (η6-alkenylarene)-
metal complexes.12 Detailed studies on the effect of the electronic
and steric properties of phosphine ligand, further modification of
the catalyst to improve activity, and the use of this metal fragment
for further catalytic reactions through π-arene intermediates are in
progress.
an (η5-alkylidenecyclohexadienyl)ruthenium structure.13 The reac-
tion of a 15 mM solution of 1a with 20 equiv of morpholine at 20
°C occurred with a pseudo-first-order kobs of 4.1 × 10-4 s-1
(monitored by 31P NMR spectroscopy) and a large ∆Sq of -213 (
5 J‚mol-1 s-1 (T ) 20-50 °C). The large negative entropy of
activation is similar to the values for the reaction of alkylamines
with nitroalkenes.14
To create a catalytic cycle, the nucleophilic attack must be
combined with a mild arene exchange process. This arene exchange
was observed in several forms. First, treatment of 3a with 40 equiv
of styrene in a mixture of dioxane and NMP at 100 °C led to a
smooth exchange of the free and coordinated arenes to afford
styrene complex 1a in the ratio of 1a:3a of >20:1 (Scheme 4).
Second, the reaction of cymene complex 2 with 40 equiv of styrene
in a mixture of dioxane and NMP at 100 °C led to nearly complete
formation of styrene complex 1a within 30 min.15
Acknowledgment. We thank the NIH-NIGMS (GM-55382) for
support of this work. J.T. thanks the JSPS for support. We also
thank Boehringer Ingelheim for an unrestricted gift.
Supporting Information Available: Experimental procedures,
product characterization and X-ray diffraction data, and procedures.
This material is available free of charge via the Internet at http://
pubs.acs.org.
A piece of spectroscopic data and two kinetic experiments
connect the arene exchange with the catalytic process. First, the
31P NMR spectra of the catalytic reaction of a 10:1 ratio of styrene
and morpholine in dioxane and NMP contained resonances at 66.3
and at 67.0 ppm, which correspond to 1a and 3a, respectively, in
ratio of ∼75:25 throughout the reaction. Consistent with the
presence of these catalytic intermediates in comparable concentra-
tions, the arene exchange between a 15 mM solution of morpholi-
noalkylarene complex 3a and 40 equiv of styrene occurred with a
first-order rate constant (kobs ) 5.6 × 10-3 s-1) that is comparable
to that for nucleophilic addition of morpholine to the η6-styrene
complex 1a at 100 °C (kobs ) 6.2 × 10-3 s-1) deduced from the
temperature-dependent rate data. Second, the reaction of styrene
with morpholine catalyzed by cymene complex 2 occurred with a
clear induction period (Figure S3), but the same reaction catalyzed
by 1a did not.
The catalytic cycle in Scheme 5 is consistent with these
mechanistic data and accounts for the anti-Markovnikov hydroami-
nation of vinylarenes catalyzed by isolated 1a and by 1a generated
in situ from Ru(COD)(2-methylallyl)2, DPPPent, and TfOH. This
mechanism includes nucleophilic addition of amine on the (η6-
styrene)ruthenium complex 1a to afford the anti-Markovnikov
adduct and arene exchange of free styrene for the coordinated arene
in (η6-(2-phenylethyl)morpholine)ruthenium complex 3a.
We sought to use these mechanistic data to improve the rates of
the catalytic reaction. Our proposed mechanism suggests that a
ruthenium complex that contains a ligand analogous to DPPPent,
but with more electron-withdrawing aryl groups on the ligand,
should undergo faster nucleophilic attack and that an analogous
complex with more hindered aryl groups on the ligand should
undergo faster arene exchange. To test these hypotheses, we
conducted the catalytic reaction with a series of analogues of
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