Dehydrogenation of aromatic amines to imines via ruthenium-catalyzed hydrogen transfer

Article abstract of DOI:10.1039/b202117j

An efficient ruthenium-catalyzed transfer dehydrogenation of amines to imines was achieved under mild conditions using 2,6-dimethoxy benzoquinone (2) or cat. 2/MnO2 as oxidant.

Full text of DOI:10.1039/b202117j

Dehydrogenation of aromatic amines to imines via ruthenium-catalyzed
hydrogen transfer
Alida H. Éll, Joseph S. M. Samec, Claudia Brasse and Jan-E. Bäckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm,
Sweden. E-mail: jeb@organ.su.se; Fax: (+46) 8-154908; Tel: (+46) 8-6747178
Received (in Cambridge, UK) 28th February 2002, Accepted 27th March 2002
First published as an Advance Article on the web 24th April 2002
Table 1 Ruthenium-catalyzed oxidation of secondary amines by 2,6-di-
An efficient ruthenium-catalyzed transfer dehydrogenation
of amines to imines was achieved under mild conditions
using 2,6-dimethoxy benzoquinone (2) or cat. 2/MnO2 as
oxidant.
methoxybenzoquinonea
We have recently studied ruthenium-catalyzed hydrogen trans-
fer reactions involving reduction of ketones to alcohols,1
oxidation of alcohols to aldehydes2 and ketones3 as well as
racemization of alcohols.4 The latter reaction was successfully
combined with enzyme catalysis to obtain dynamic kinetic
resolution (DKR).5 We6 and others7 have also studied the
corresponding transfer hydrogenation of imines but to our
knowledge no hydrogen transfer-based procedure for oxidation
of amines to imines has been reported.8,9 The latter process is of
general synthetic interest and also important for racemization of
amines10 under transfer hydrogen conditions involving dehy-
drogenation of amine to imine and readdition of hydrogen.
In this manuscript we report on a novel procedure for the
oxidation of amines to imines via a ruthenium-catalyzed
hydrogen transfer. The reaction proceeds in refluxing toluene
with 111 as catalyst and quinone 2 as hydrogen acceptor. It is
also demonstrated that the quinone can be used as electron
transfer mediator (ETM) in catalytic amounts employing an
external oxidant for recycling of the hydroquinone to quinone
2.
Time Yieldb
Entry
Substrate
R
R’
(h)
(%)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
Ph
Ph
Ph
Ph
Ph
5
6
2
2
2
2
1.5
70
71
95
93
95
90
93
p-F-C6H4
p-Me-C6H4
p-MeO-C6H4
Ph
p-MeO-C6H4
o-Me-C6H4
p-MeO-C6H4
Ph
3g
p-MeO-C6H4
a The reaction was performed on a 0.5 mmol scale in refluxing toluene (4
mL) with 2 mol% of 1 and 1.5 equiv. of 2. b Determined by 1H NMR
spectroscopy.
and the selectivity for the corresponding imines was > 99% in
all cases. Unfortunately, this system failed to catalyze the
oxidation of nonaromatic amines. This is probably due to the
lower thermal stability of the corresponding nonaromatic imine.
When compared to ruthenium-catalyzed dehydrogenation of
alcohols, the reaction rate of amines is much slower and harsher
conditions are required in order to achieve high conver-
sions.13
(1)
The use of the system MnO2/catalytic amount of quinone 2
(Scheme 1) was also successfully applied to the oxidation of a
number of substituted aromatic amines 3 (Table 2).
It was demonstrated in a control experiment that the process
with manganese dioxide (Scheme 1) requires the presence of
quinone 2. Without 2 the conversion of 3 to 4 was < 9% after 24
hours. The amount of MnO2 did not effect the rate but the
variation of 2 did. At low concentrations of quinone the rate is
proportional to the ratio quinone 2/catalyst 1, whereas at higher
quinone concentrations the rate becomes independent of this
ratio. A few other quinones were also tried. Concerning the
activity of the tested p-benzoquinone derivatives, we found that
electron-rich quinones are more active in the catalytic system.
Oxidation of N-phenyl-N-(1-phenylethyl)amine (3a) was
studied under various reaction conditions employing 1 as
catalyst and quinone 2 as hydrogen acceptor. From a survey of
solvents, toluene was found to be the most efficient. Thus,
oxidation of 3a in toluene employing 2 mol% of 1 and 1.5 equiv.
of quinone 2 afforded 4a in 70% yield after 5 hours (Table
1).
When the amount of 1 was lowered to 1 mol%, the rate of the
reaction slightly decreased. In the absence of 1 no imine
formation was observed. A number of different secondary
amines were oxidized by quinone 2 employing this catalytic
system (Table 1). We found that electronic variation of the
amine substrate has an effect on the efficiency of the
dehydrogenation reaction. As can be seen from Table 1, amines
3c–3g having electron-donating substituents (entries 3–7) on
any of the aromatic rings reacted faster than 3a, and gave a high
yield of imine. On the other hand, an electron-withdrawing
substituent has a negative influence on the outcome of the
oxidation (entry 2), and led to a lower reaction rate.
This new catalytic oxidation via low-valent ruthenium-
catalyzed hydrogen transfer gives remarkably clean reactions
Scheme 1 A coupled catalytic system for dehydrogenation of secondary
amines.
1144
CHEM. COMMUN., 2002, 1144–1145
This journal is © The Royal Society of Chemistry 2002

a
Table 2 Ruthenium-catalyzed oxidation of secondary amines by MnO2
equiv. of 2. Since our experiments were carried out with 1.5
equiv. of 2 we conclude that there is no pre-equilibrium under
these conditions and the isotope effect should originate from the
dehydrogenation.
A likely intermediate in the dehydrogenation of 3a is the
amine complex 5, which after b-hydride abstraction by the
metal would give the imine. Attempts to isolate 5 have so far
been unsuccessful. However, the primary amine complex 615
was prepared and it was demonstrated that it acts as a catalyst in
the amine dehydrogenation reaction according to eqn. (1).16
Time Yieldb
Entry Substrate
R
R’
(h)
(%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
Ph
Ph
Ph
Ph
Ph
5
5
5
5
5
5
4
4
76
70
83
94
91
90
94
90
p-F-C6H4
p-Me-C6H4
p-MeO-C6H4
Ph
p-MeO-C6H4
o-Me-C6H4
p-MeO-C6H4
2,4,6-triMe-C6H4
Ph
3g
3h
p-MeO-C6H4
Ph
a The reaction was performed on a 0.5 mmol scale in refluxing toluene (0.5
mL) with 2 mol% of 1, 20 mol% of 2 and 1.5 equiv. of MnO2 b Determined
by 1H NMR spectroscopy.
Our novel coupled catalytic system via ruthenium-catalyzed
hydrogen transfer provides a new method for selective oxida-
tion of secondary amines to the corresponding imines. The
amine is dehydrogenated by a ruthenium catalyst and the Ru-
hydride produced reacts with p-benzoquinone to give hydro-
quinone. At present the recycling of the hydroquinone is
demonstrated by the use of MnO2, and in this way the quinone
becomes an electron transfer mediator (ETM). The use of air or
molecular oxygen for this recycling is currently being stud-
ied.
Financial support from the Swedish Natural Science Re-
search Council, the Swedish Research Council for Engineering
Sciences and the Swedish Foundation for Strategic Research is
gratefully acknowledged.
It is interesting to note that in all cases the reaction proceeds
significantly faster with quinone 2 as terminal oxidant com-
pared to the coupled catalytic system with cat. 2/MnO2 (Scheme
1), even though the reaction mixture is four times more diluted
because of the low solubility of 2.
The deuterium isotope effect for the amine to imine oxidation
was determined by comparing the rates for dehydrogenation of
a-deuterio-3a and 3a (Scheme 2). The reaction was run with 1.5
equiv. of 2 to amine and without MnO2. The ratio of the rates for
the reaction was determined at low conversions (initial rate
method). An isotope effect of kH/kD = 3.5 was obtained.12 In
principle this isotope effect may originate from the dehydroge-
nation step (3a ? 4a) or from addition of hydrogen to quinone
2.
Notes and references
1 R. L. Chowdhury and J.-E. Bäckvall, J. Chem. Soc., Chem. Commun.,
1991, 1063.
2 J.-E. Bäckvall, R. L. Chowdhury and U. Karlsson, J. Chem. Soc., Chem.
Commun., 1991, 473.
3 (a) G.-Z. Wang, U. Andreasson and J.-E. Bäckvall, J. Chem. Soc.,
Chem. Commun., 1994, 1037; (b) M. L. S. Almeida, M. Beller, G.-Z.
Wang and J.-E. Bäckvall, Chem. Eur. J., 1996, 2, 1533.
4 F. F. Huerta, A. B. E. Minidis and J.-E. Bäckvall, Chem. Soc. Rev., 2001,
30, 321.
5 B. A. Persson, A. L. E. Larsson, M. LeRay and J.-E. Bäckvall, J. Am.
Chem. Soc., 1999, 121, 1645.
Scheme 2 Observed deuterium isotope effect for the amine to imine
oxidation.
6 G.-Z. Wang and J.-E. Bäckvall, J. Chem. Soc., Chem. Commun., 1992,
980.
7 (a) E. Mizushima, M. Yamaguchi and T. Yamagishi, Chem. Lett., 1997,
237; (b) N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya and R. Noyori,
J. Am. Chem. Soc., 1996, 118, 4916; (c) J. Mao and D. C. Baker, Org.
Lett., 1999, 1, 841.
8 Oxidation of amines by high valent ruthenium has been reported: (a) A.
J. Bailey and B. R. James, J. Chem. Soc., Chem. Commun., 1996, 2343;
(b) S.-I. Murahashi, Angew. Chem. Int. Ed. Engl., 1995, 34, 2443; (c) S.-
I. Murahashi, T. Naota and H. Taki, J. Chem. Soc., Chem. Commun.,
1985, 613; (d) P. Müller and D. M. Gilabert, Tetrahedron Lett., 1988,
44, 7171.
9 For other methods for oxidation of amines to imines see: (a) J. P. Marino
and R. D. Larsen, J. Am. Chem. Soc., 1981, 103, 4642; (b) J. J. Cornejo,
K. D. Larson and G. D. Mendenhall, J. Org. Chem., 1985, 50, 5382.
10 (a) M. T. Reetz and K. Schimmosek, Chimia, 1996, 50, 668; (b) M. J.
Hateley, D. A. Schichl, H.-J. Kreuzfeld and M. Beller, Tetrahedron
Lett., 2000, 41, 3821; (c) Y. K. Choi, M. J. Kim, Y. Ahn and M.-J. Kim,
Org. Lett., 2001, 3, 4099.
11 Y. Blum and Y. Shvo, J. Organomet. Chem., 1985, C7.
12 The reported isoptope effect kH/kD for addition of 1b (RuH/RuD) to
benzaldehyde is 1.5: C. P. Casey, S. W. Singer, D. R. Powell, R. K.
Hayashi and M. Kavana, J. Am. Chem. Soc., 2001, 123, 1090.
13 G. Csjernyik, A. H. Éll, L. Fadini, B. Pugin and J.-E. Bäckvall, J. Org.
Chem., 2002, 67, 1657.
14 Equilibrium isotope effects are usually much smaller than kinetic
isotope effects.
15 M. Abed, I. Goldberg, Z. Stein and Y. Shvo, Organometallics, 1988, 7,
The following equations [eqns. (2) and (3)] are involved
where Q is quinone 2, HQ the corresponding hydroquinone and
1a and 1b are the two halves of catalyst 1 shown in Scheme 1.
(2)
(3)
There is no doubt that k2 > > k1. This follows from the fact that
the turnover frequency (TOF) for recycling benzoquinone 2 to
its hydroquinone is > 4000 h21 13
In the present system the
.
overall TOF is 50 h21, which requires that the dehydrogenation
is the slow step. Now if k2[Q] > k21 [4a] we will have an
irreversible rate-determining dehydrogenation of 3a to 4a and
the isotope effect will originate from that step. In this case the
overall rate will be independent of the quinone concentration.
However, if k2[Q] < k1 [4a] there will be a pre-equilibrium and
the isotope effect would have to originate from the addition of
ruthenium hydride to quinone and also from the equilibrium of
eqn. (2).14 In the latter case the rate of the reaction will depend
on the concentration of quinone.
One way to distinguish between the two different possibilities
is to determine if there is a dependence or not of the quinone 2
on the rate. We found that the rate of dehydrogenation of 3a is
independent of quinone for 2/1 > 40, i.e. with more than 0.8
2054.
16 b-Hydride abstraction from 6 gives the active catalyst.
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