Ruthenium-catalyzed intermolecular coupling reactions of arylamines with ethylene and 1,3-dienes: Mechanistic insight on hydroamination vs ortho-C-H bond activation

Article abstract of DOI:10.1021/ol050524+

(Chemical Equation Presented) The cationic ruthenium complex [(PCy ₃)₂(CO)(Cl)Ru=CHCH=C(CH₃)₂] ⁺BF₄^- was found to be an effective catalyst for the coupling reaction of aniline and ethylene to form a ～1:1 ratio of N-ethylaniline and 2-methylquinoline products. The analogous reaction with 1,3-dienes resulted in the preferential formation of Markovnikov addition products. The normal isotope effect of k_NH/k_ND = 2.2 (aniline and aniline-d₇ at 80°C) and the Hammett ρ = -0.43 (correlation of para-substituted p-X-C₆H₄NH₂) suggest an N-H bond activation rate-limiting step for the catalytic reaction.

Full text of DOI:10.1021/ol050524+

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2181-2183
Ruthenium-Catalyzed Intermolecular
Coupling Reactions of Arylamines with
Ethylene and 1,3-Dienes: Mechanistic
Insight on Hydroamination vs ortho-C
−H
Bond Activation
Chae S. Yi* and Sang Young Yun
Department of Chemistry, Marquette UniVersity, Milwaukee, Wisconsin 53201-1881
chae.yi@marquette.edu
Received March 10, 2005
ABSTRACT
+
-
The cationic ruthenium complex [(PCy3)2(CO)(Cl)Ru
aniline and ethylene to form a 1:1 ratio of N-ethylaniline and 2-methylquinoline products. The analogous reaction with 1,3-dienes resulted
in the preferential formation of Markovnikov addition products. The normal isotope effect of kNH/kND 2.2 (aniline and aniline-d7 at 80 C) and
H bond activation rate-limiting step for the catalytic
dCHCHdC(CH3)2] BF4 was found to be an effective catalyst for the coupling reaction of
∼
)
°
the Hammett G ) −0.43 (correlation of para-substituted p-X-C6H4NH2) suggest an N
−
reaction.
Transition metal-catalyzed hydroamination of alkenes and
alkynes is a highly effective method for forming new C-N
bonds.1 Though early transition and lanthanide metal catalysts
have been successfully utilized for hydroamination reactions,2
late transition metal catalysts have been shown to be
particularly promising for the functionalized substrates. Since
Milstein’s pioneering example of Ir-catalyzed hydroamina-
tion reaction of norbornene,3 a number of late transition metal
catalysts have been developed for the hydroamination
reactions. Most notably, Hartwig recently developed highly
effective chiral Pd-phosphine catalysts for the asymmetric
version of hydroamination of aryl-substituted alkenes and
dienes.4 Ozawa and co-workers developed highly active
cationic Pd-allyl catalysts for the hydroamination of 1,3-
dienes.5 Furthermore, several groups recently achieved anti-
Markovnikov hydroamination reactions of R-olefins6 and
intramolecular hydroamination of unactivated alkenes7 by
using late metal catalysts. One of the remaining challenges
for the hydroamination reaction is to develop practical
catalytic systems that can lead to an extension of a relatively
(1) Recent reviews: (a) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98,
675. (b) Taube, R. In Applied Homogeneous Catalysis with Organometallic
Compounds; Cornils, B., Herrmann, W. A., Eds.; VCH: New York, 1996.
(c) Brunet, J. J.; Neibecker, D. In Catalytic Heterofunctionalization from
Hydroamination to Hydrozirconation; Togni, A., Gru¨tzmacher, H., Eds.;
Wiley-VCH: New York, 2001. (d) Roesky, P. W.; Mu¨ller, T. E. Angew.
Chem., Int. Ed. 2003, 42, 2708.
(2) Recent examples of early transition metals: (a) Shi, Y.; Ciszewski,
J. T.; Odom, A. L. Organometallics 2001, 20, 3967. (b) Ackermann, L.
Organometallics 2003, 22, 4367. (c) Knight, P. D.; Munslow, I.;
O’Shaughnessy, P. N.; Scott, P. Chem. Commun. 2004, 894. Examples of
lanthanide metals: (d) Tian, S.; Arredondo, V. M.; Stern, C. L.; Marks, T.
J. Organometallics 1999, 18, 2568. (e) Hong, S.; Marks, T. J. J. Am. Chem.
Soc. 2002, 124, 7886. (f) Hong, S.; Tian, S.; Metz, M. V.; Marks, T. J. J.
Am. Chem. Soc. 2003, 125, 14768. (g) Ryu, J.-S.; Li, G. Y.; Marks, T. J.
J. Am. Chem. Soc. 2003, 125, 12584.
(3) Casalnuovo, A. L.; Calabrese, J. C.; Milstein, D. J. Am. Chem. Soc.
1988, 110, 6738.
(4) (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546.
(b) Lo¨ber, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
4366. (c) Hartwig, J. F. Pure Appl. Chem. 2004, 76, 507.
(5) Minami, T.; Okamoto, H.; Ikeda, S.; Tanaka, R.; Ozawa, F.; Yoshifuji,
M. Angew. Chem., Int. Ed. 2001, 40, 4501.
(6) (a) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126,
2702. (b) Sanford, M. S.; Groves, J. T. Angew. Chem., Int. Ed. 2004, 43,
588.
(7) (a) Kim, Y. K.; Livinghouse, T.; Horino, Y. J. Am. Chem. Soc. 2003,
125, 9560. (b) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005,
127, 1070.
10.1021/ol050524+ CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/30/2005

narrow reaction scope and are applicable to organic synthesis.
We recently developed a new catalytic method for forming
synthetically useful cyclic imines from the C-H bond
activation reaction of cyclic amines and alkenes.8 In an effort
to extend the scope of the catalytic reaction, we have begun
to explore the catalytic activity of ruthenium complexes for
the hydroamination of alkenes and dienes.
amination reactions.10 The catalytic synthesis of quinoline
derivatives is of considerable interest in part due to their
biological and pharmacological importance.11
The scope of the reaction was surveyed by using the
catalyst 1 (Table 2). Both primary arylamines and secondary
Table 2. Hydroamination of Ethylene and 1,3-Dienesa
We previously found that the cationic ruthenium-alkyl-
idene complex [(PCy3)2(CO)(Cl)RudCH-CHdC(CH3)2]+-
-
BF4 (1) is an effective catalyst for hydrovinylation and
silylation reactions.9 Initially, we explored the catalytic
activity of 1 for the hydroamination of alkenes. For example,
the treatment of aniline (60 mg, 0.65 mmol) with ethylene
(7 mmol) in the presence of 1 (5 mol %) in benzene at
80 °C gave a ∼1:1 mixture of N-ethylaniline (2a) and
2-methylquinoline (3a) in 71% combined yield (eq 1). The
organic products 2a and 3a were isolated by column
chromatography, and their structures were completely es-
tablished by spectroscopic methods.
The survey of ruthenium catalysts showed that the cationic
ruthenium complexes, 1 and that formed in situ from (PCy3)2-
(CO)(Cl)RuH (4)/HBF4‚OEt2,9a were found to be equally
effective for the hydroamination of aniline and ethylene
(Table 1). The addition of excess acid marginally influenced
Table 1. Coupling Reaction of Aniline and Ethylenea
2a
3a
entry
catalyst
additive (mol %) (% yield)b (% yield)b
1
2
3
4
5
6
7
8
9
1
4
4
4
4
4
34
<1
38
40
1
<1
0
37
0
HBF4‚OEt2 (10)
HBF4‚OEt2 (20)
CF3SO3H (10)
NH4Cl (10)
40
28
4
a Reaction conditions: amine (0.65 mmol), alkene (6-7 mmol), 1 (5
mol %), benzene (2-5 mL). b Isolated yield. c 4 (5 mol %)/HBF4‚OEt2 (10
mol %) was used as the catalyst.
0
(PPh3)3RuHCl
(PPh3)3RuHCl
[(PCy3)2(CH3CN)2-
(CO)RuH]BF4
Ru3(CO)12
RuCl3‚3H2O
[Ru(cod)Cl2]x
0
HBF4‚OEt2 (10)
0
0
1
1
benzocyclic amines were found to be suitable substrates for
the hydroamination reaction. A mixture of the hydroamina-
tion and the quinoline products 2 and 3 was formed for aryl-
substituted amines (entries 1-3), while the reaction of
indoline with ethylene gave a mixture of 2d and the dehydro-
genation product 4d (entry 4). Only ethylene was found to
give the coupling products among selected alkenes; no
activity was observed with alkyl-substitued alkenes and
styrene.
10
11
12
NH4PF6 (15)
HBF4‚OEt2 (10)
HBF4‚OEt2 (10)
<1
<1
<1
0
0
<1
a Reaction conditions: aniline (0.3 mmol), ethylene (6 mmol), Ru catalyst
(5 mol %), benzene (2 mL), 80 °C, 48 h. b Determined by GC.
the product ratio of 2a and 3a for the reactions catalyzed by
4/HBF4‚OEt2 (entries 3, 4). A salient feature of 1 is that the
catalyst does not require any acids or other additives to effect
the catalytic reaction. The formation of 2-methylquinoline
products has been previously reported in metal-catalyzed
(10) (a) Diamond, S. E.; Szalkiewicz, A.; Mares, F. J. Am. Chem. Soc.
1979, 101, 490. (b) Beller, M.; Thiel, O. R.; Trauthwein, H.; Hartung, C.
G. Chem. Eur. J. 2000, 6, 2513. (c) Brunet, J.-J.; Cadena, M.; Chu, N. C.;
Diallo, O.; Jacob, K.; Mothes, E. Organometallics 2004, 23, 1264.
(11) (a) Balasubramanian, M.; Keay, J. G. In ComprehensiVe Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996; Vol. 5, p 245. (b) Jones, G. In Compre-
hensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Pergamon Press: Oxford, 1996; Vol. 5, p 167.
(8) Yi, C. S.; Yun, S. Y.; Guzei, I. A. Organometallics 2004, 23, 5392.
(9) (a) Yi, C. S.; Lee, D. W.; Chen, Y. Organometallics 1999, 18, 2043.
(b) Yi, C. S.; He, Z.; Lee, D. W.; Rheingold, A. L.; Lam, K.-C.
Organometallics 2000, 19, 2036. (c) He, Z.; Yi, C. S.; Donaldson, W. A.
Org. Lett. 2003, 5, 1567.
2182
Org. Lett., Vol. 7, No. 11, 2005

The hydroamination reaction of butadiene proceeded at a
considerably lower temperature to form the Markovnikov
addition product 5e predominantly over the anti-Markovni-
kov addition product 6e (entries 5 and 6). High regioselec-
tivity for the Markovnikov addition products was observed
for substituted 1,3-dienes, albeit with moderate yields (entries
7-9). No ortho-C-H bond activation product was observed
for these dienes.
Scheme 1
To discern the factors influencing the formation of
hydroamination vs C-H bond activation products, the
following mechanistic studies were performed by using
aniline and ethylene. (1) The empirical reaction rate was
found to be first-order with respect to both [aniline] and [1]
and was independent of [ethylene] for a wide range of
concentrations (3.2-13.5 mM) (Supporting Information).
The rate constant kobs ) 3.4 × 10-2 h-1 was obtained under
pseudo-first-order reaction conditions at [aniline] ) 0.65 mM
and [1] ) 32 µM.
(2) A normal deuterium isotope effect was observed for
the reaction of C6H5NH2 and C6D5ND2. The pseudo-first-
order plots of the catalytic reaction from both aniline and
subsequent ethylene insertion, â-H elimination, reinsertion,
and reductive elimination steps would lead to the 2-methyl
tetrahydroquinoline product, which further undergoes
ruthenium-promoted dehydrogenation to form the quinoline
product 3.13 The apparent lack of the formation of quinoline
products for 1,3-dienes can be readily explained by the
preferential formation of a sterically demanding secondary
allyl intermediate species from 2,1-insertion of a diene, which
would prohibit the ortho-C-H bond activation.14
In summary, the cationic ruthenium complex 1 was found
to be an effective catalyst for the hydroamination of ethylene
and 1,3-dienes. The formation of a nearly equal ratio of
products 2 and 3 is explained by an initial N-H bond
activation rate-limiting step followed by energetically com-
patible reductive elimination vs ortho-C-H bond activation
pathways. Further research is warranted for a detailed
understanding on the factors influencing the ortho-C-H bond
activation of arylamines.
aniline-d7 at 80 °C led to kobs ) 2.9 × 10-2 h-1 and kobs
)
)
1.3 × 10-2 h-1, respectively, which translated to kNH/kND
2.2 ( 0.1 at 80 °C (Figure S1, Supporting Information). A
similar normal deuterium isotope effect has been observed
on the distribution of both products, 2a vs 2a-d and 3a vs
3a-d. In contrast, a negligible isotope effect of kCH/kCD was
observed from C6H5NH2 and C6D5NH2 with ethylene at 80
°C. These results indicate that the N-H bond activation is
the rate-limiting step of the catalytic reaction and the
subsequent ortho-C-H bond and alkene insertion steps are
relatively facile.
(3) The reaction rate was found to be moderately acceler-
ated by an electron-releasing group of aniline. A Hammett
value F of -0.43 was obtained from the correlation of para-
substituted p-X-C6H4NH2 (X ) OMe, CH3, H, CF3) with
σp+ (Figure S6, Supporting Information). A better correlation
+
Acknowledgment. Financial support from the National
Institutes of Health, General Medical Sciences (R15
GM55987), is gratefully acknowledged.
with σp compared to σp suggests the importance of
resonance stabilization in the cationic transition state.12
A possible mechanistic scheme of the catalytic reaction
is shown in Scheme 1. Both the observation of the normal
isotope effect of kNH/kND ) 2.2 and the Hammett value F )
-0.43 support a mechanism with the N-H bond activation
as the rate-limiting step, in which the N-H bond activation
step is promoted by an electron-releasing group. The
subsequent alkene insertion and the reductive elimination via
an alkyl-amido species 7 would give the product 2. The zero-
order dependence on [ethylene] suggests that the alkene
insertion step is rapid and reversible. The formation of
2-methylquinoline product 3 can be rationalized by invoking
a competitive ortho-arene C-H bond activation from 7. The
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of organic products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL050524+
(13) Treatment of tetrahydroquinoline with ethylene and 1 (5 mol %)
gave the quinoline product 3a. A similar result was also reported in ref
10a.
(14) Observed Hammett and the kinetic isotope effect data are also
consistent with a mechanism involving reversible nucleophilic addition of
aniline to a cationic (π-alkene)Ru species followed by rate-limiting proton
transfer, though this mechanism cannot readily explain the formation of
quinoline products.4,5 A “domino” mechanism of sequential addition of
alkenes via an imine intermediate has been proposed for the formation of
quinoline products.10b
(12) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry Part
A: Structure and Mechanism, 3rd Ed.; Plenum Press: New York, 1990.
Org. Lett., Vol. 7, No. 11, 2005
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