Iron(ii)-bis(isonitrile) complexes: Novel catalysts in asymmetric transfer hydrogenations of aromatic and heteroaromatic ketones

Article abstract of DOI:10.1039/c0cc00508h

Chiral iron(ii)-bis(isonitrile) complexes catalyse the transfer hydrogenation of aromatic ketones with enantioselectivities up to 91% ee, most likely via hydride transfer through imine intermediates, generated by in situ reduction of the isonitrile ligands, whereas iron acts as a Lewis acid to activate the ketone.

Full text of DOI:10.1039/c0cc00508h

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Iron(II)–bis(isonitrile) complexes: novel catalysts in asymmetric transfer
hydrogenations of aromatic and heteroaromatic ketonesw
Anu Naik, Tapan Maji and Oliver Reiser*
Received 20th March 2010, Accepted 6th May 2010
First published as an Advance Article on the web 20th May 2010
DOI: 10.1039/c0cc00508h
Chiral iron(II)Àbis(isonitrile) complexes catalyse the transfer
hydrogenation of aromatic ketones with enantioselectivities up
to 91% ee, most likely via hydride transfer through imine
intermediates, generated by in situ reduction of the isonitrile
ligands, whereas iron acts as a Lewis acid to activate the ketone.
The application of iron, being the most abundant metal on
earth, in homogeneous catalysis has recently gained considerable
attention,1,2 promising the substitution of more precious
metals such as palladium, rhodium or ruthenium. The latter
two transition metals build the edifice for asymmetric transfer
hydrogenations of ketones3,4 as one of the most appealing
Scheme 1 Synthesis of iron(II)–bis(isonitrile) complexes 2a–e.
synthetic routes to chiral alcohols that avoids molecular
hydrogen or hydrides as reducing agents. There have been
several successful attempts to develop iron catalyst for transfer
hydrogenations,5 which has recently culminated in the
spectacular break through by Morris and co-workers who
disclosed the first asymmetric version applying iron complexes
containing P–N–N–P tetradentate ligands.6,7
Based on our interest to utilize chiral oxazolines as synthetic
building blocks for chiral ligands,8 we recently reported the
synthesis of a new kind of bis(isonitriles) 1a–c and their
corresponding palladium complexes, which showed good
activities in non-stereoselective Wacker oxidations.9 Herein
we report iron complexes of those ligands and demonstrate for
the first time the potential of isonitriles as chiral ligands
with the asymmetric transfer hydrogenation of aromatic and
heteroaromatic ketones.
Fig. 1 X-Ray structure of Fe(2b)2(SnCl3)2 (Cl atoms on Sn were
omitted for clarity).
Bidentate bis(isonitrile) ligands (BINC) 1a–e could readily
be synthesized from amino alcohols in two steps following the
protocol developed by us earlier for 1a–c.9 The corresponding
iron(II) complexes were obtained by treatment of 1a–e with
FeCl2Á4H2O in methanol,10 which led to the formation of
orange coloured FeCl2(BINC)2 complexes (2a–e) in good
yields (Scheme 1).
result in a distorted octahedral complex (Fig. 1). Notably, the
iron–isonitrile unit has by and large a linear geometry (1691)
with Fe–C and isonitrile C–N bond lengths averaging 1.86 A
and 1.14 A, respectively, indicating that no or little back
bonding from the metal to the ligand takes place.11
Complexes 2a–e were tested as catalysts for transfer hydrogen-
ation of acetophenone using isopropanol as the hydrogen
source under basic conditions (Table 1, entries 1–5). Complex
2b was identified to be an active catalyst at room temperature
(entry 2) giving rise to 1-phenylethanol with 90% conversion
and 64% ee, demonstrating for the first time the applicability
of isonitrile ligands as chiral inductors in asymmetric catalysis.
The substitution pattern in the isonitrile ligands appears to
play an important role to render 2 an efficient catalyst in
transfer hydrogenations. While the isopropyl derivative 2c still
showed appreciable activity and selectivity (Table 1, entry 3),
the benzyl complex 2a and derivatives 2d and 2e being
substituted at the b-position of the isonitrile were by and large
inactive. Since we assume (vide infra) that both iron and the
isonitrile moiety play an integral role in the hydride transfer to the
Exchanging the chloride with trichlorostannyl ligands by
reacting 2b with SnCl2 allowed insights into the structure of
iron(II)–BINC complexes. X-Ray analysis of the so obtained
Fe(2b)2(SnCl3)2 revealed that the bidentate isonitrile ligands
had coordinated iron(II) in a square planar geometry with the
trichlorostannyl ligands taking the axial positions to overall
Institut fur Organische Chemie, Universitat Regensburg,
¨
¨
Universitatsstr. 31, 93053 Regensburg, Germany.
¨
E-mail: oliver.reiser@chemie.uni-regensburg.de;
Fax: +49 941 943 4121; Tel: +49 941 943 4631
w Electronic supplementary information (ESI) available: Experimental
details and spectroscopical data of 2b and catalytic reactions
performed. CCDC 771169. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0cc00508h
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Table 1 Transfer hydrogenation of aromatic ketones with catalysts
2a–2e
Table 2 Transfer hydrogenation of heteroaromatic and pyridyl
ketones catalyzed by 2b
Entry
Ketone
Time/h
Conv. %a
ee %b
ee
%
b
Entry Ar
Catalyst Time/h Conv. %a
1
2
3
2-acetylfuran
3
1
3
6
1
1
24
3
>99
70
36
85
95
30
1
2
Ph
Ph
2a
2b
2c
2d
2e
2b
2b
2b
2b
2b
2b
23
8
8
24
24
12
1
24
6
17
90
71
6
24
94
>99
60
50
93
56
n.d.
64
54
10
17
60
67
67
58
54
52
64
64
2-acetylthiophene
3-acetylthiophene
2-acetylpyridine
3-acetylpyridine
4-acetylpyridine
53 (S)
62
41
3
4
Ph
Ph
4
5c
6
61
5
Ph
99
80
55 (S)
91
72
6c
7c
8c
9c
10c
11c
12c
13
p-Cl–Ph
m-Cl–Ph
o-Br–Ph
p-OMe–Ph
m-OMe–Ph
o-OMe–Ph
7d,e
8e
R = H
R = Ph
98
9e
R = Cl
15
93
89
84
52
1
3
10e
6
Phenylethylketone 2b
2-Acetonaphthone 2b
6
1
73
84
14c
2b
3
62
46
11d
24
83
83
a
b
Determined by GC using decane internal standard. Determined by
a
b
Determined by GC using decane internal standard. Determined by
c
HPLC. 0.05 M i-PrOH.
c
HPLC. 0.1 M concentration of substrate. 0.2 M concentration of
e
substrate. Isolated yield.
d
ketone, small conformational changes in the iron–bis(isonitrile)
complexes might sufficiently disturb the required arrangement
of these two moieties to give catalytic turnover. Control
experiments with various nickel or copper salt/2b combinations
did not give rise to any ketone reduction under the reaction
conditions, clearly attributing the asymmetric process described
here to iron catalysis.
pyridine nitrogen is in proximity or even interacting with the
active centre of the catalyst. The resulting chiral pyridyl
alcohols are useful intermediates in the synthesis of ligands
for asymmetric catalysis.12 To the best of our knowledge only
kinetic resolutions13 of racemic pyridyl alcohols were reported
by Pfaltz and co-workers but there has been no report on the
asymmetric hydrogenation of pyridyl ketones so far.
Catalyst 2b was subsequently applied to other aromatic
methyl ketones, giving rise to the corresponding alcohols with
overall similar enantioselectivity ranging from 52 to 67% ee.
We noticed, however, considerable rate differences in the
reductions: meta-substituted aromatic ketones, either with
donor (Table 1, entry 10) or acceptor groups (Table 1, entry 7),
as well as 2-acetonaphthone (Table 1, entry 13) turned out to
be most reactive. Noteworthy in light of pyridine substituted
ketones discussed below, constricting the carbonyl group
within a six-membered ring (entry 14) did not result in an
improvement of enantioselectivity.
To gain insight into the mechanism on how the iron–
bis(isonitrile) complexes are operating, we carried out some
IR experiments (Fig. 2). The spectrum of a solution of
iron–bis(isonitrile) complex 2b in isopropanol (7 mmol lÀ1
)
shows a broad absorption of the isonitrile NC group at higher
frequency (2177 cmÀ1, Fig. 2B) than that of the free bis(isonitrile)
ligand 1b (2140 cmÀ1, Fig. 2A). The high value of n(NC) is
attributed to the strong s-bonding interaction between the
isonitrile carbon and the charged metal centre. The solution of
2b in iPrOH was then treated with 10 equivalents of t-BuOK,
resulting in the complete disappearance of the isonitrile
band within 10 minutes and the appearance of a new band
at 1638 cmÀ1 (Fig. 2C). The latter is assigned to the presence of
a CQN double bond, indicating the reduction of isonitrile to
the corresponding imine. In contrast, we could find no indication
for a Fe–H band, which would have been expected14 around
1900 cmÀ1. Moreover, in NMR studies no signals at negative
ppm, typical for such species, were observed.
Turning to heteroaromatic methylketones (Table 2, entries
1–6), we observed high turn over for the carbonyl reduction,
allowing reaction times as little as one hour to achieve
complete conversion. Enantioselectivities remained moderate,
however, a reversal of the absolute stereochemistry in the
products with respect to the aromatic ketones was observed
with the exception of 2-acetylthiophene (Table 2, entry 2) and
4-acetylpyridine (Table 2, entry 6).
Using pyridyl ketones in which the carbonyl group was
embedded into a cyclic system (entries 7–11) dramatically
improved the enantioselectivities, giving rise to the corres-
ponding alcohols in up to 91% ee. It was interesting to note
that a substituent in 2-position is detrimental to the enantio-
selectivity (entries 8–10), which might be an indication that the
Therefore, we propose that the reaction proceeds by a type
of Meerwein–Ponndorf–Verley mechanism as shown in
Scheme 2, being different from the reported mechanisms for
transfer hydrogenations with ruthenium involving achiral
isonitrile ligands.15 We speculate that the ketone binds via
its carbonyl group or alternatively through the respective
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heteroatom in the case of heteroaromatic substrates to the
iron centre of the catalyst. Hydride transfer then occurs
directly from the reduced isonitrile group acting as the
hydrogen donor.
In conclusion, we developed a new type of iron catalyst
being effective in asymmetric transfer hydrogenations of
ketones. The noteworthy feature of the iron complexes
employed in our study are coordinating isonitrile groups that
might serve as acceptors for hydrogen that is subsequently
delivered to the ketone being activated by the iron centre. In
addition, this is the first report that demonstrates the ability of
isonitriles to be able to serve as chiral ligands in asymmetric
catalyses.
This work was supported by the DAAD (fellowships for
AN and TM), the Fonds der Chemischen Industrie, and
Degussa Rexim. We thank Dr Manfred Zabel and Sabine
Stempfhuber, Department of Crystallography, University
of Regensburg, for carrying out the X-ray structure analysis
of 2b.
Notes and references
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Fig. 2 IR spectra in i-PrOH: (A) free ligand 1b; (B) iron complex 2b;
(C) iron complex 2b in the presence of 10 equiv. t-BuOK.
7 A. A. Mikhailine, A. J. Lough and R. H. Morris, J. Am. Chem.
Soc., 2009, 131, 1394.
8 (a) H. Werner, R. Vicha, A. Gissibl and O. Reiser, J. Org. Chem.,
2003, 68, 10166; (b) M. Seitz, A. Kaiser, A. Tereshchenko,
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10 Cf. J. A. Kargol and R. J. Agelici, Inorg. Chim. Acta, 1983, 68,
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11 For the first characterization of an iron complex with monodentate
isonitrile units with a Fe(NCR)4Sn2 core see W. W. Brennessel and
J. E. Ellis, Angew. Chem., Int. Ed., 2007, 46, 598.
12 (a) S. Kaiser, S. P. Smidt and A. Pfaltz, Angew. Chem., Int. Ed.,
2006, 45, 5194; (b) Y. Xie, H. Huang, W. Mo, X. Fan, Z. Shen,
N. Sun, B. Hu and X. Hu, Tetrahedron: Asymmetry, 2009, 20,
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8, 1879.
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J. Am. Chem. Soc., 1985, 107, 5581; (b) C. Bianchini, M. Peruzzini
and F. Zanobini, J. Organomet. Chem., 1988, 354, C19.
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J. Gimeno, Organometallics, 2004, 23, 4836; Leading reviews:
(b) R. Noyori and T. Ohkuma, Angew. Chem., Int. Ed., 2001, 40,
40; (c) S. E. Clapham, A. Hadzovic and R. H. Morris, Coord.
Chem. Rev., 2004, 248, 2201.
Scheme 2 Proposed mechanism for iron(II)–bis(isonitrile) catalyzed
transfer hydrogenations.
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Chem. Commun., 2010, 46, 4475–4477 | 4477