Biomimetic transfer hydrogenation of ketones with iron porphyrin catalysts

Article abstract of DOI:10.1016/j.tetlet.2006.09.058

For the first time in situ generated iron porphyrins have been applied as homogeneous catalysts for the transfer hydrogenation of ketones. Using 2-propanol as hydrogen source various ketones are reduced to the corresponding alcohols in good to excellent yield and selectivity. Under optimized reaction conditions high catalyst turnover frequencies up to 642 h^-1 are achieved.

Full text of DOI:10.1016/j.tetlet.2006.09.058

Tetrahedron Letters 47 (2006) 8095–8099
Biomimetic transfer hydrogenation of ketones with iron
porphyrin catalysts
Stephan Enthaler, Giulia Erre, Man Kin Tse, Kathrin Junge and Matthias Beller*
Leibniz-Institut f u¨ r Katalyse e.V. an der Universit a¨ t Rostock, Albert-Einstein-Str. 29a, D-18059 Rostock, Germany
Received 17 July 2006; revised 11 September 2006; accepted 12 September 2006
Available online 4 October 2006
Abstract—For the first time in situ generated iron porphyrins have been applied as homogeneous catalysts for the transfer hydro-
genation of ketones. Using 2-propanol as hydrogen source various ketones are reduced to the corresponding alcohols in good to
À1
excellent yield and selectivity. Under optimized reaction conditions high catalyst turnover frequencies up to 642 h are achieved.
Ó 2006 Elsevier Ltd. All rights reserved.
Alcohols are key intermediates for the synthesis of phar-
maceuticals, agrochemicals, polymers and new materi-
to industrial applications. To the best of our knowledge
7
8
9
only the groups of Noyori, Vancheesan, Bianchini
1
,2
10
als.
Starting from carbonyl compounds various
and Gao reported the utilization of iron salts and iron
complexes in the reduction of a,b-unsaturated carbonyl
compounds and ketones. For tuning the activity and
selectivity of these catalysts, oxygen and moisture sensi-
catalytic approaches toward the synthesis of alcohols
have been developed. Typical examples are the addition
of organometallic compounds to aldehydes, hydrosilyl-
2
9
10
ation, and hydrogenation of aldehydes or ketones.
tive tetradentate phosphines or aminophosphines
Among these transformations hydrogenations represent
the most atom-efficient and environmentally benign
methodology. In particular, transfer hydrogenation is
a powerful strategy because of the ease of performance
and general applicability. More specifically, a broad
scope of alcohols is available by transfer hydrogenation
using non-toxic hydrogen donors, for example, 2-propa-
have been predominantly applied as ligands.
Inspired by nature we thought that multidentate nitro-
gen ligands should be also suitable ligands for stabilizing
iron as metal centre in transfer hydrogenations. In the
past biomimetic ligand toolboxes were invented, which
are based on natural sources or similar structural motifs,
for example, amino alcohols, quinidines, bisoxazolines
3
nol or HCOOH/NEt , under mild reaction conditions in
3
1
1
the presence of precious metal catalysts based on Ir, Rh,
and porphyrins.
Within these potential ligands,
4
Ru, or Ni.
porphyrins, which are involved in manifold biological
redox processes, seemed of special interest to us due to
their strong ability to stabilize the iron centre.
1
2,13
With regard to the upcoming catalyst developments a
fundamental challenge is the substitution of these expen-
sive and rare transition metals by less toxic, inexpensive
Stimulated by our ongoing research in catalytic hydro-
5
15
and abundantly available metals such as iron. Until
genations we became interested in developing new
now, homogeneous iron catalysts have been most fre-
quently applied for carbon–carbon coupling reactions,
such as olefin polymerizations, cross-couplings and cyc-
hydrogenation catalysts based on iron. Thus, we report
herein for the first time a combination of iron and por-
phyrins as catalysts for the efficient reduction of various
ketones (Scheme 1).
6
loadditions as well as reductions of nitro compounds.
However, much less attention was directed toward
iron-catalyzed (transfer) hydrogenations, although the
relevance of such reductions is evident even with respect
In exploratory experiments, 2-propanol-based transfer
hydrogenation of acetophenone was examined using
an easy to adopt in situ catalyst system comprising
Fe (CO) and porphyrin 1a. Typically, the active cata-
3
12
*
Corresponding author. Tel.: +49 381 1281 113; fax: +49 381 1281
000; e-mail: matthias.beller@catalysis.de
lyst is prepared by stirring a solution of 1 mol % iron
source and 1 mol % 1a in 2-propanol (1.0 mL) for 16 h
5
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.058

8096
S. Enthaler et al. / Tetrahedron Letters 47 (2006) 8095–8099
14
Scheme 1. Selection of applied porphyrins.
at 65 °C. After the addition of 50 mol % base the
mixture is heated for 5 min at 100 °C and the standard
Interestingly, the transfer hydrogenation proceeds
highly chemoselectively (>99%). In no case significant
amounts (>1%) of by-products (e.g., aldol condensation
products) are obtained.
1
6
substrate acetophenone 4 is added.
Initially, the influence of temperature and various bases
on the reaction rate was investigated. An optimal cata-
lyst activity is obtained at 100 °C (Table 1, entries 1–
Next, attempts were made concerning the iron source
1
7
(Table 2).
The best activity was obtained for
1
8
3
). In general, sodium and potassium alkoxides gave
Fe (CO) , FeBr , Fe(acac) and [Et NH][HFe(CO) ].
3
12
2
3
3
4
an excellent yield of 1-phenylethanol (96–99%, Table
, entries 4–8). Noteworthy from a practical point of
view is that NaOH and K CO also led to a high prod-
1
Surprisingly, no reliable correlation between the oxida-
tion state and reaction rate was observed as high activity
was detected for Fe(0)-, Fe(II)- and Fe(III)-salts. Hence,
the formation of the active catalyst species is complete
for the various pre-catalysts under the applied condi-
tions. However, studying the dependency of conversion
versus reaction time in the presence of Fe (CO)
2
3
uct yield. However, in the presence of organic bases such
as NEt and pyridine (Table 1, entries 10 and 11) no
3
significant amount of product is formed in reasonable
time. Diminishing the base concentration resulted in a
decrease of 1-phenylethanol. In the absence of a base,
no transfer of hydrogen was observed.
3
12
revealed an induction period of nearly 2 h.
Table 1. Catalytic transfer hydrogenation of acetophenone 4
Table 2. Influence of iron sources in the transfer hydrogenation of
acetophenone 4
a
Entry Iron source Base
Temperature (°C) Yield (%)
1
2
3
4
5
6
7
8
9
1
1
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
3
3
3
3
3
3
3
3
3
3
3
(CO)12
(CO)12
(CO)12
(CO)12
(CO)12
(CO)12
(CO)12
(CO)12
(CO)12
(CO)12
(CO)12
2-PrONa
2-PrONa
2-PrONa 100
NaOH
KOH
LiOH
80
90
56
68
96
98
42
5
99
97
89
<1
<1
a
Entry
Iron source
Fe (CO)12
FeBr
Yield (%)
100
100
100
100
1
2
3
4
5
6
7
8
9
3
96
98
90
86
74
97
44
46
97
2
FeCl
FeCl
2
3
K-t-OBu
Na-t-OBu 100
Fe(acac)
Fe(acac)
2
K
2
CO
NEt
Pyridine
3
100
100
100
3
0
1
3
CpFe(CO)
FeSO
4
[Et NH][HFe(CO) ]
2
I
4
3
Standard reaction conditions: 0.0038 mmol in situ catalyst
0.0013 mmol Fe (CO)12 and 0.0038 mmol 1a in 2.0 mL 2-propanol for
6 h at 65 °C), 0.19 mmol base, 5 min at described temperature, then
the addition of 0.38 mmol acetophenone 4, 7 h at described
(
1
3
Standard reaction conditions: 0.0038 mmol in situ catalyst
(0.0038 mmol Fe-source or 0.0013 mmol Fe (CO)12 and 0.0038 mmol
1a in 2.0 mL 2-propanol for 16 h at 65 °C), 0.19 mmol base, 5 min at
100 °C, then the addition of 0.38 mmol acetophenone 4, 7 h at 100 °C.
3
temperature.
a
a
Yield and conversion were determined by GC analysis (50 m Lipodex
Yield and conversion were determined by GC analysis (50 m Lipodex
E, 95–150 °C) with diglyme as an internal standard.
E, 95–150 °C) with diglyme as an internal standard.

S. Enthaler et al. / Tetrahedron Letters 47 (2006) 8095–8099
8097
In the case of Fe(acac)2 and Fe(acac) a favourable
Table 4. Fe-catalyzed reduction of various ketones in the presence of
porphyrins 1b and 1e
3
conversion was observed for the Fe(III)-salt. Comparing
the results of FeCl and FeBr , a small influence of the
2
2
corresponding halide was also detected.
Next, we focused our attention on the influence of the
metal–ligand ratio. Even without any ligand some cata-
lytic activity is obtained (54% of 5). The addition of 0.5
or 0.2 equiv of 1a (with respect to Fe) increased the yield
of 1-phenylethanol to 74% and 86%, respectively. The
highest yield is obtained at a metal–ligand ratio of 1:1.
A further increase of the number of ligand with respect
to iron (2:1) resulted in a slight decrease of activity (89%
of 5).
a
a
Entry
1
Product
1b Yield (%)
1e Yield (%)
46
72
2
>99
>99
In order to further improve the catalyst system, we
applied different porphyrin ligands (1a–3) in the model
reaction in the presence of 0.5 mol % Fe catalyst
3
4
93
50
95
68
(
Fe (CO) , sodium 2-propylate, 100 °C). As shown in
3
12
Table 3, best yields were achieved with meso-substituted
porphyrins 1b and 1e (Table 3, entries 3 and 6). Substi-
tution in the meso-phenylic system of porphyrin 1b with
electron withdrawing groups (1a, 1c, and 1d) displayed a
decrease in activity (Table 3, entries 1, 3 and 4).
In addition, porphyrins substituted in the b-pyrrolenic
positions were employed in the reduction of acetophe-
none. The activity of the symmetric coproporphyrin I
5
6
92
21
87
22
2
was to some extend lower when compared with
meso-substituted porphyrins. The natural complex chlo-
roprotoporphyrin IX Fe(III) 3 was utilized without cat-
alysts pre-formation as described for all other ligands,
and a moderate yield of 1-phenylethanol was detected
7
8
9
<1
<1
89
90
(
Table 3, entry 8). Nevertheless, complex 3 is an interest-
ing catalyst for such reactions due to easier handling and
availability.
b
b
26 [71]
11 [55]
Table 3. Testing of different porphyrins in the transfer hydrogenation
of acetophenone 4
Standard reaction conditions: 0.0038 mmol in situ catalyst (0.0013
mmol Fe (CO)12 and 0.0038 mmol porphyrin in 2.0 mL 2-propanol for
6 h at 65 °C), 0.19 mmol sodium 2-propylate, 5 min at 100 °C, then
3
1
a
À1 b
)
Entry Porphyrin Catalyst
loading (mol %)
Yield (%)
TOF (h
addition of the corresponding ketone (0.76 mmol), 7 h at 100 °C.
a
Conversion was determined by GC analysis (entry 1 (25 m Lipodex E,
8
3
9
0–180 °C), entries 2, 6, 8 and 9 (30 m, HP Agilent Technologies, 50–
00 °C), entry 3 (25 m Lipodex E, 100 °C), entry 4 (50 m Lipodex E,
0–105 °C), entry 5 (25 m Lipodex E, 90–180 °C), entry 7 (50 m
1
2
3
4
5
6
7
8
1a
1a
1b
1c
1d
1e
2
0.5
90
45
93
68
56
94
45
51
26
642
27
19
16
27
13
15
0.01
0.5
0.5
0.5
0.5
0.5
0.5
Lipodex E, 90–180 °C)) with diglyme as internal standard.
In brackets the results after 24 h reaction time.
b
In order to demonstrate the utility of our concept, we
selected ligand 1b and 1e and used the correspond-
ing Fe pre-catalysts in the reduction of nine aliphatic
and aromatic ketones (Table 4). When using 0.5 mol %
pre-catalyst in the presence of 50 mol % sodium 2-pro-
pylate, most substrates were hydrogenated in a good
yield. Only disappointing activities were obtained for ke-
tones substituted adjacent to the carbonyl group by a
chloromethyl or a cyclopropyl group (Table 4, entries
3
Standard reaction conditions: 0.0038 mmol or 0.000038 mmol in situ
catalyst (0.0013 mmol or 0.000013 mmol Fe (CO)12 and 0.0038 mmol
or 0.000038 mmol porphyrin in 2.0 mL 2-propanol for 16 h at 65 °C),
.19 mmol or 0.0019 mmol sodium 2-propylate, 5 min at 100 °C, then
the addition of 0.76 mmol acetophenone 4, 7 h at 100 °C.
Conversion was determined by GC analysis (50 m Lipodex E, 95–
3
0
a
1
50 °C) with diglyme as an internal standard.
Turnover frequencies were determined after 7 h.
b

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S. Enthaler et al. / Tetrahedron Letters 47 (2006) 8095–8099
6
and 7). Comparing different substitutions on the
In Transition Metals for Organic Synthesis, 2nd ed.; Beller,
M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004; pp 145–
66; (d) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.;
Studer, M. Adv. Synth. Catal. 2003, 345, 103–151; (e)
Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226–
phenyl ring no reliable relationship between electron
donating and electron withdrawing substituents and
activity was observed (Table 4, entries 1–4). Similar to
the model reaction, in all cases conversion and yield
were nearly identical.
1
2
36; (f) Samec, J. S. M.; B a¨ ckvall, J.-E.; Andersson, P. G.;
Brandt, P. Chem. Soc. Rev. 2006, 35, 237–248.
4
. Selected recent examples of transfer hydrogenations: (a)
Schlatter, A.; Kundu, M. K.; Woggon, W.-D. Angew.
Chem., Int. Ed. 2004, 43, 6731–6734; (b) Xue, D.; Chen,
Y.-C.; Cui, X.; Wang, Q.-W.; Zhu, J.; Deng, J.-G. J. Org.
Chem. 2005, 70, 3584–3591; (c) Wu, X.; Li, X.; King, F.;
Xiao, J. Angew. Chem., Int. Ed. 2005, 44, 3407–3411; (d)
Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J.
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In agreement with previous findings the highest yield is
obtained with 2-methoxyacetophenone due to the pres-
ence of a second coordination site.
1
9
In addition to aryl alkyl ketones, we also examined more
challenging dialkyl ketones in this iron-catalyzed trans-
fer hydrogenation. Good conversion and yield (89–
9
0%) were observed for both substrates applying an iron
catalyst containing 1e as ligand. In general, ligand 1e
gave better results compared to 1b. This effect is espe-
cially pronounced for the dialkyl substrates (Table 4,
entries 8 and 9).
4
4, 6214–6219.
5
. Due to the widespread abundance of iron in earth’s crust
and the easy accessibility the current price of iron is
relatively low (approximately 300 US-dollar/t) compared
to rhodium, iridium or ruthenium. Furthermore, iron is an
essential trace element (daily dose for humans 5–28 mg)
and is involved in an extensive number of biological
processes.
In conclusion, we have demonstrated for the first time
the successful application of in situ prepared iron
porphyrin catalysts in the transfer hydrogenation of
ketones. The catalyst system is easily prepared and mim-
ics biologically occurring Fe complexes. Under opti-
6
. Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev.
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À1
mized conditions turnover frequencies up to 642 h
3
were achieved. The scope and limitation of the catalyst
were demonstrated on the reduction of nine different
ketones with good to excellent yields.
8
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Acknowledgements
Dong, Z.-R.; Li, Y.-Y.; Gao, J.-X. Huaxue Xuebao 2004,
6
2, 1745–1750.
This work has been financed by the State of Mecklen-
burg-Western Pomerania, the Bundesministerium f u¨ r
Bildung und Forschung (BMBF) and the Deutsche
Forschungsgemeinschaft (Leibniz-award). We thank
Mr. B. Hagemann, Mrs. C. Mewes, Mrs. M. Heyken,
Mrs. S. Buchholz, and Dr. C. Fischer (all Leibniz-Insti-
tut f u¨ r Katalyse e.V. an der Universit a¨ t Rostock) for
their excellent technical and analytical support.
1
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rin 1a (0.0038 mmol) is dissolved in 1.0 mL 2-propanol
and stirred for 16 h at 65 °C. Then a solution of sodium 2-
propylate (0.19 mmol) in 0.5 mL 2-propanol is added. The
solution is stirred for 5 min at 100 °C followed by the
addition of 0.38 mmol acetophenone 4. After 7 h at
100 °C, the mixture is cooled to rt and filtered over a plug
of silica gel. The conversion and yield were determined
by GC without further purification. All synthesized
alcohols are known compounds. Their characterization
is done by a comparison with authentic samples.
17. Sodium 2-propylate was chosen due to easier handling.
18. Dahl, L. F.; Blount, J. F. Inorg. Chem. 1965, 4, 1373–
1375.
1
6. All experiments were carried out under an inert gas
atmosphere (argon) with exclusion of air. For the standard
19. Enthaler, S.; Hagemann, B.; Erre, G.; Junge, K.; Beller,
M. Chem. Asian J. 2006, 1, in press.