Iron-catalyzed Reductive Amination of Aldehydes and Ketones with Anilines
essary for the reductive amination of aldehydes. Ortho-,
meta- and para-substituted benzaldehydes with electron-do-
Experimental Section
All experiments were done in 4 mL glass vials. Brand-new glass vials
were placed in a Parr Instruments 4560 series autoclave (300 mL) con-
taining an alloy plate that holds seven 4 mL glass vials.
nating and electron-withdrawing groups were reacted in
high yields (Table 3, entries 1–12). Noteworthy, keto- and
ester-goups were tolerated and the aldehyde reacted selec-
tively to form the corresponding amines (Table 3, entries 9
and 10, respectively). The catalytic activity did not decrease
by applying sterically demanding aldehydes, such as 2,4,6-tri-
methylbenzaldehyde 4c (Table 3, entry 3). Furthermore, an
excellent product yield of 90% was obtained with thio-
phene-2-carbaldehyde 4k, whilst the reductive amination of
pyridine-3-carbaldehyde did not furnish the desired product,
probably owing to the coordination of pyridine to the iron
catalyst. Finally, the reductive amination of different amines
with benzaldehyde 4a was investigated. Ortho-, meta- and
para-substituted anilines with electron-donating and elec-
tron-withdrawing groups reacted with benzaldehyde under
hydrogenative conditions in high yields of 95% (Table 4).
General Procedure for the Hydrogenative Reductive Amination of
Ketones
A: A vial was charged under an argon atmosphere with ketone
1
(0.5 mmol), 4-anisidine 2a (0.75 mmol), Fe3(CO)12 (0.02 mmol), 3 ꢃ mo-
lecular sieves (200 mg), dry toluene (1.0 mL), and a magnetic stirring bar
and capped with a septum which was equipped with a needle. The vial
was placed in the alloy plate, which was then placed into the pre-dried
autoclave. Once sealed, the autoclave was purged 3 times with hydrogen,
then pressurized to 50 bar, heated at 658C, and stirred for 24 h. The auto-
clave was cooled to 58C, depressurized, the reaction mixture was trans-
ferred into a flask, evaporated under reduced pressure, and the residue
was purified by column chromatography on silica gel (eluent: heptane/
ethyl acetate 20:1 to 10:1) to give the corresponding amine 3.
B: A vial was charged under an argon atmosphere with ketone
1
(0.5 mmol), 4-anisidine 2b (0.75 mmol), 3 ꢃ molecular sieves (200 mg),
dry toluene (1.0 mL), and a magnetic stirring bar and capped with a
septum. The mixture was stirred for 16 h at room temperature. Fe3(CO)12
(0.02 mmol) was added, the vial was placed in the alloy plate, which was
then placed into the pre-dried autoclave. Once sealed, the autoclave was
purged 3 times with hydrogen, then pressurized to 50 bar, and heated at
658C for 24 h. The autoclave was cooled to 58C, depressurized, the reac-
tion mixture was transferred into a flask, evaporated under reduced pres-
sure, and the residue was purified by column chromatography on silica
gel (eluent: heptane/ethyl acetate 20:1 to 10:1) to give the corresponding
amine 3.
Table 4. Reductive amination of benzaldehyde with different anilines.
General Procedure for the Hydrogenative Reductive Amination of
Aldehydes
A
vial was charged under an argon atmosphere with aldehyde
4
(0.5 mmol), 4-anisidine 2a or amine (0.75 mmol), Fe3(CO)12
2
(0.02 mmol), dry toluene (1.0 mL), and a magnetic stirring bar and
capped with a septum which was equipped with a needle. The vial was
placed in the alloy plate, which was then placed into the pre-dried auto-
clave. Once sealed, the autoclave was purged 3 times with hydrogen,
then pressurized to 50 bar, heated at 658C, and stirred for 24 h. The auto-
clave was cooled to 58C, depressurized, the reaction mixture was trans-
ferred into a flask, evaporated under reduced pressure, and the residue
was purified by column chromatography on silica gel (eluent: heptane/
ethyl acetate 20:1 to 10:1) to give the corresponding amine 5 or 6.
1H, and 13C spectra were recorded on Bruker spectrometers AVANCE
300 (1H: 300.13 MHz, 13C: 75.5 MHz, 31P: 121.5 MHz). The calibration of
1H and 13C spectra was carried out on solvent signals (d, CDCl3)=7.26
and 77.0). Chemical shifts are given in ppm, coupling constants are re-
ported in Hz. Mass spectra were recorded on an AMD 402 spectrometer.
Elemental analyses were performed at a Leco CHNS-932. IR spectra
were recorded as ATR on a BRUKER ALPHA-P. All manipulations
were performed under an argon atmosphere using standard Schlenk tech-
niques.
Unfortunately, under optimized conditions the reaction of
aliphatic amines, such as n-butylamine or 2-ethylhexylamine,
with benzaldehyde 4a gave only the corresponding imine
and no hydrogenation was observed. On the other hand,
secondary amines, such as N-benzylaniline can be used to
gain access to tertiary amines.
In summary, we have reported the first homogeneous
iron-based catalyst system for the reductive amination of al-
dehydes and ketones using molecular hydrogen. Whilst nu-
merous precious-metal-based catalysts are known, iron has
been scarcely investigated in such catalytic reductions.
More specifically, we demonstrated that inexpensive triir-
on dodecacarbonyl can catalyze the direct hydrogenative re-
ductive amination of carbonyl compounds with various ani-
lines without the need of any special or expensive ligand.
Good to excellent yields of 68–97% have been achieved for
a range of aryl, alkyl, and heterocyclic ketones as well as al-
dehydes with primary and secondary anilines.
Acknowledgements
This work has been funded by the State of Mecklenburg-Western Pomer-
ania, the BMBF, and the DFG (Liebniz-prize). S.F. thanks the Evonik
a grant. The authors thank Dr. C. Fischer, S. Buchholz,
S. Schareina, and S. Smyczek (all at the Leibniz-Institut fꢁr Katalyse e.V.)
for their excellent analytical and technical support.
Stiftung for
Keywords: amines · catalysis · iron · ketones · reductive
amination
Chem. Asian J. 2011, 6, 2240 – 2245
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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