Mechanistic investigation on the hydrogenation of imines by [p-(Me 2CH)C6H4Me]RuH(NH2CHPhCHPhNSO 2C6H4-p-CH3). Experimental support for an ionic pathway

Article abstract of DOI:10.1039/b605838h

The need for acidic activation in the stoichiometric hydrogenation of benzyl-[1-phenyl-ethylidene]-amine (6a) or [1-(4-methoxy-phenyl)-ethylidene]- methyl-amine (6b) by Noyori's catalyst [p-(Me₂CH)C₆H ₄Me]RuH(NH₂CHPhCHPhNSO₂C₆H ₄-p-CH₃) (2) is inconsistent with the proposed concerted mechanism and supports an ionic mechanism. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b605838h

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Mechanistic investigation on the hydrogenation of imines by
p-(Me CH)C H Me]RuH(NH CHPhCHPhNSO C H -p-CH ).
Experimental support for an ionic pathway
[
2
6
4
2
2 6
4
3
˚
Jenny B. Aberg, Joseph S. M. Samec and Jan-E. B a¨ ckvall*
Received (in Cambridge, UK) 25th April 2006, Accepted 23rd May 2006
First published as an Advance Article on the web 6th June 2006
DOI: 10.1039/b605838h
The need for acidic activation in the stoichiometric hydrogena-
tion of benzyl-[1-phenyl-ethylidene]-amine (6a) or [1-(4-meth-
oxy-phenyl)-ethylidene]-methyl-amine (6b) by Noyori’s
catalyst [p-(Me CH)C H Me]RuH(NH CHPhCHPhNSO -
2
6
4
2
2
6 4 3
C H -p-CH ) (2) is inconsistent with the proposed concerted
mechanism and supports an ionic mechanism.
Optically active compounds are important in the fine-chemical,
1
pharmaceutical, and agrochemical industries. Chiral amines can
Fig. 2 Proposed cyclic transition state for hydrogenation of ketones and
imines.
be prepared by catalytic reduction of imines, and transfer
hydrogenation has been used successfully for both imines and
5
alcohols. The concerted pathway is supported by kinetic isotope
2,3
ketones. In transfer hydrogenation, an alcohol, e.g. 2-propanol,
12
measurements carried out by Casey et al. and calculations
or a formate is used as hydrogen source. After our report of Ru-
4
catalysed transfer hydrogenation of imines by 2-propanol, the
13
performed by the groups of Noyori, Andersson, and van
14
15
Leeuwen. While mechanistic studies have been extensive for
first asymmetric transfer hydrogenation of imines was reported by
5
Noyori et al. In the latter reaction HCOOH was employed as the
ketones/alcohols, the studies on the corresponding reaction
involving imines/amines are limited. It has merely been assumed
that both classes of compounds follow the same mechanistic
hydrogen donor. Chiral Ru(II)–TsDPEN complex 1 (Fig. 1) was
used as catalyst in transfer hydrogenation of both ketones and
imines to give quantitative yields and high enantioselectivities (ee’s
7,13
pathway.
16
17
We and Casey et al. have recently shown that for the related
metal ligand bifunctional catalyst 4, transfer hydrogenation of
imines (Scheme 1) occurs via a different mechanism to that of
ketones.
3,5–7
up to 97% for imines).
Some additional recent contributions of transfer hydrogenation
8
9
10
11
of imines include Ru(II)-, Rh(III)-, Ir(III)-, and Ni(0)- catalysts.
No asymmetric transfer hydrogenation of imines using 2-propanol
as hydrogen donor has been reported.
Here we report that the concerted mechanism proposed for
addition of hydride 2 to ketones (aldehydes) and imines (Fig. 2) is
not operating for imines. The hydride species 2, which reacts fast
with ketones (aldehydes), does not react with imines. However,
when an acid is added in the latter case a fast reduction occurs.
These results support an ionic mechanism for the reduction of
imines by 1, where the substrate is pre-activated by protonation
prior to hydrogen transfer. Recently, an ionic mechanism has been
proposed by Norton and Bullock for the hydrogenation of ketones
The proposed mechanism for transfer hydrogenation of ketones
and imines by 2, formed from 1, involves a cyclic transition state
(A) where the hydride and the proton are transferred from the
catalyst to the substrate in a concerted reaction without
6,7
coordination of the substrate (Fig. 2).
The mechanism has been studied by several groups. Noyori and
co-workers have isolated 2 and 3 and proven that they are the
active species in catalysis involving ketones (aldehydes) and
18
(aldehydes) and imines by different transition metal catalysts.
2
-Propanol alone cannot be used as the terminal reductant in
5
the transfer hydrogenation of imines catalyzed by 1. Instead a
mixture of formic acid and triethylamine is used. We argued that
this may be due to product inhibition where the amine produced
Fig. 1 Noyori’s Ru–TsDPEN catalyst precursor 1, true catalyst 2 and
reactive intermediate 3.
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, SE-106 91 Stockholm, Sweden. E-mail: jeb@organ.su.se;
Fax: +46-8-154908; Tel: +46-8-674 7178
Scheme 1 Studied reaction between Shvo’s catalyst 4 and imines.
Chem. Commun., 2006, 2771–2773 | 2771
This journal is ß The Royal Society of Chemistry 2006

View Article Online
a
Table 1 Addition of acid is necessary for reduction of imine 6a by 2 .
b
c
Time/h Conversion (%) Ee (%)
d
Entry Acid
pK
a
1
2
3
4
5
6
7
8
9
1
1
1
1
a
HCOOH
HCOOH
3.75
3.75
0.5
1
23
1
23
1
23
1
23
1
96
96
. 99
. 99
39
73
39
78
. 99
. 99
26
29
—
91
85
78
75
69
84
94
89
80
78
82
80
—
HBF
HBF
4
4
0.5
CF
CF
3
COOH 0.52
COOH 0.52
Scheme 2 Stoichiometric reaction between 2 and imine 6 does neither
3
form any complex, nor reduce the substrate.
CH COOH 4.76
3
CH COOH 4.76
3
Sc(OTf)
Sc(OTf)
3
0
1
2
3
3
23
23
coordinates to 3, formed from 2, to give a stable Ru–amine
complex.{ To investigate this complexation we mixed stoichio-
metric amounts of 2 with an imine. To our surprise, neither a Ru–
amine complex, nor free amine was observed (Scheme 2, Path A).
PhCOOH
4.2
Me
—
3
COOH 5.03
—
23
e
31
Unless otherwise noted, 35 mmol of imine was mixed with acid
1 equiv. followed by 2 2 equiv. in CH Cl under argon. The reaction
mixture was worked up with 2 M NaOH, extracted with CH
Both the chemical shifts and the integrals (400 MHz, CD
Cl ) of
2 2
2
2
2
b
Cl
2
,
the hydride signal of 2 at d 25.87 (s, 1 H) and the benzyl
hydrogens at d 4.66 (s, 2 H) and methyl group at d 2.29 (s, 3 H) of
imine 6a remained unchanged. In a similar experiment with imine
dried (Na
2
SO
4
)
values apply to dilute aqueous solutions and are taken from ref. 19.
and purified by bulb-to-bulb distillation. pK
a
c
d
Conversion determined by NMR.
determined by GC analysis. 4 equiv. of 2 were used.
(S)-configuration, ee
e
6b the signals of the methyl groups of the imine at d 3.83 (s, 3 H),
d 3.29 (s, 3 H) and d 2.19 (s, 3H) also remained unchanged. The
singlet of ferrocene at d 4.12 was used as an internal standard.
Even with a large excess of imine (10 equiv.) no reaction
between hydride 2 and the imine occurred after 12 hours
The Swedish Research Council is gratefully acknowledged for
financial support.
(Scheme 2, path A).{,§ This is in sharp contrast to the reaction
of ketones, where treatment of 2 with a tenfold excess of acetone
Notes and references
(
R 5 Me Scheme 2, path B) instantaneously gave the 16 electron
6
species 3 and 2-propanol. Since formic acid/triethylamine is used
{
The corresponding Ru–amine complexes of bifunctional catalyst 4 have
recently been reported by us and Casey, see refs. 16 and 17.
Slow decomposition of the hydride was detected, but this also occurred in
for catalytic transfer hydrogenation of imines we argued that the
activation barrier is too high to overcome without acidic activation
of the imine by protonation. This was supported by the fact that
addition of one equivalent of formic acid to the reaction mixture
afforded the corresponding amine (Table 1, entry 1).
{
the absence of imine.
§ To prove that this was not due to unfavorable thermodynamics, attempts
were made to study the reverse reaction by mixing the coordinatively
2 2
unsaturated 16 electron species 3 and amine 7a in CD Cl . A tenfold excess
1
of amine did not produce any detectable amounts (by H NMR) of
dehydrogenation products.
To confirm that the formic acid was not working as hydrogen
donor we performed the hydrogenation of imines 6 by 2 with
different Brønsted acids and one Lewis acid. Interestingly, most of
these acids worked well to promote the hydrogenation. The use of
tetrafluoroboric acid afforded the amine in excellent yield (Table 1,
entry 3). Trifluoroacetic as well as acetic acid gave high yields after
prolonged reaction times (Table 1, entries 6 and 8). Scandium
triflate, which has been used for activation of imines in reductive
1 A. N. Collins, G. N. Sheldrake and J. Crosby, Editors, Chirality
in Industry II: Developments in the Commercial Manufacture and
Applications of Optically Active Compounds, Wiley, Chichester, 1997.
2
J. S. M. Samec, J.-E. B a¨ ckvall, P. G. Andersson and P. Brandt, Chem.
Soc. Rev., 2006, 35, 237; S. Gladiali and E. Alberico, Chem. Soc. Rev.,
2006, 35, 226; H.-U. Blaser, C. Malan, B. Pugin, F. Spindler,
H. Steiner and M. Studer, Adv. Synth. Catal., 2003, 345, 103;
S. E. Clapham, A. Hadzovic and R. H. Morris, Coord. Chem. Rev.,
20
amination, also gave an excellent yield in the reaction between
imine 6a and catalyst 2 (Table 1, entry 9). This further supports the
proposal that the role of the acid is to activate the imine. Only the
sterically hindered benzoic and pivalic acid gave moderate yields in
this transformation (Table 1, entries 11 and 12). The striking
difference when using no acid is still evident, since no amine is
formed, even after 31 hours (Table 1, entry 13). All yields and ee
values are comparable to those of the catalytic version (cf. 72%
2
004, 248, 2201.
3 R. Noyori, M. Yamakawa and S. Hashiguchi, J. Org. Chem., 2001, 66,
931.
G. Z. Wang and J.-E. B a¨ ckvall, J. Chem. Soc., Chem. Commun., 1992,
80.
7
4
5
6
9
N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya and R. Noyori, J. Am.
Chem. Soc., 1996, 118, 4916.
K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya and R. Noyori, Angew.
Chem., Int. Ed. Engl., 1997, 36, 285.
R. Noyori and S. Hashiguchi, Acc. Chem. Res., 1997, 30, 97.
E. Mizushima, M. Yamaguchi and T. Yamagishi, J. Mol. Catal. A:
Chem., 1999, 148, 69; J. S. M. Samec and J.-E. B a¨ ckvall, Chem.–Eur. J.,
7
8
5
yield and 77% ee after 36 h).
Based on our studies, we conclude that the concerted pathway
7,13
2002, 8, 2955.
previously reported (Fig. 2) does not operate for imines. Acidic
activation of the imine is required and further studies on how the
protonated imine is hydrogenated by hydride 2 are currently
underway.
9
J. Mao and D. C. Baker, Org. Lett., 1999, 1, 841; M. Albrecht,
R. H. Crabtree, J. Mata and E. Peris, Chem. Commun., 2002, 32.
0 J. R. Miecznikowski and R. H. Crabtree, Polyhedron, 2004, 23,
1
2857.
2
772 | Chem. Commun., 2006, 2771–2773
This journal is ß The Royal Society of Chemistry 2006

View Article Online
1
1
1
1 S. Kuhl, R. Schneider and Y. Fort, Organometallics, 2003, 22, 4184.
2 C. P. Casey and J. B. Johnson, J. Org. Chem., 2003, 68, 1998.
3 M. Yamakawa, H. Ito and R. Noyori, J. Am. Chem. Soc., 2000, 122,
466.
4 D. A. Alonso, P. Brandt, S. J. M. Nordin and P. G. Andersson, J. Am.
Chem. Soc., 1999, 121, 9580.
17 C. P. Casey, S. W. Singer, D. R. Powell, R. K. Hayashi and M. Kavana,
J. Am. Chem. Soc., 2001, 123, 1090; C. P. Casey and J. B. Johnson,
J. Am. Chem. Soc., 2005, 127, 1883.
18 R. M. Bullock, Chem.–Eur. J., 2004, 10, 2366; M. P. Magee and
J. R. Norton, J. Am. Chem. Soc., 2001, 123, 1778; H. Guan, M. Iimura,
M. P. Magee, J. R. Norton and G. Zhu, J. Am. Chem. Soc., 2005, 127,
7805; M. Schlaf, P. Ghosh, P. J. Fagan, E. Hauptman and
R. M. Bullock, Angew. Chem., Int. Ed., 2001, 40, 3887.
19 D. R. Lide, CRC Handbook of Chemistry and Physics, CRC Press, Boca
Raton, Florida, 86th edn, 2005.
20 T. Itoh, K. Nagata, A. Kurihara, M. Miyazaki and A. Ohsawa,
Tetrahedron Lett., 2002, 43, 3105.
1
1
1
5 D. G. I. Petra, J. N. H. Reek, J.-W. Handgraaf, E. J. Meijer, P. Dierkes,
P. C. J. Kamer, J. Brussee, H. E. Schoemaker and P. W. N. M. van
Leeuwen, Chem.–Eur. J., 2000, 6, 2818.
1
6 J. S. M. Samec, A. H. Ell and J.-E. B a¨ ckvall, Chem. Commun., 2004,
748; A. H. Ell, J. B. Johnson and J.-E. B a¨ ckvall, Chem. Commun.,
003, 1652.
2
2
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 2771–2773 | 2773