Selective hydrogenation of aromatic aminoketones by Pd/C catalysis

Article abstract of DOI:10.1080/00397910801993719

We report an alternative hydrogenation of aromatic aminoketones by heterogeneous catalyst of palladium on carbon (Pd/C) in which nitro, in particular carbonyl groups in the ketones, could be selectively transformed to corresponding amino ketone, secondary alcohol, or methylene compound. Copyright Taylor & Francis Group, LLC.

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Selective Hydrogenation of
Aromatic Aminoketones by Pd/
C Catalysis
Rui Du a , Changjin Zhu a , Peilong Zhang a & Ruizhen
Fan a
a Department of Applied Chemistry , Beijing
Institute of Technology , Beijing, China
Published online: 28 Aug 2008.
To cite this article: Rui Du , Changjin Zhu , Peilong Zhang & Ruizhen Fan (2008)
Selective Hydrogenation of Aromatic Aminoketones by Pd/C Catalysis, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:17, 2889-2897, DOI: 10.1080/00397910801993719
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Synthetic Communications1, 38: 2889–2897, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801993719
Selective Hydrogenation of Aromatic
Aminoketones by Pd/C Catalysis
Rui Du, Changjin Zhu, Peilong Zhang, and Ruizhen Fan
Department of Applied Chemistry, Beijing Institute of Technology,
Beijing, China
Abstract: We report an alternative hydrogenation of aromatic aminoketones
by heterogeneous catalyst of palladium on carbon (Pd=C) in which nitro, in
particular carbonyl groups in the ketones, could be selectively transformed to
corresponding amino ketone, secondary alcohol, or methylene compound.
Keywords: Aromatic aminoketone, chemoselectivity, heterogeneous catalysis,
hydrogenation, Pd=C catalyst
INTRODUCTION
Reduction of ketones to secondary alcohols is an important transformation
in organic synthesis.[1,2] Chemical reduction and catalytic reduction are the
two common ways to do this. Chemical reduction is a convenient method in
which metal hydride reagents such as sodium borohydride are often used.[2]
However, a large amount of metal sludge is formed in the reaction.
In recent years, much attention has been paid to the research of cata-
lytic hydrogenation of carbonyl compounds using a homogeneous cata-
lyst because of the low cost, lack of formation of metal sludge, and in
particular the introduction of asymmetric chemistry into the hydrogen-
ation of carbonyl compounds.[3] However, few heterogeneous catalytic
hydrogenation methods of ketones to alcohols have been reported.[4,5]
Commonly, when palladium on carbon (Pd=C) is used to catalyze the
hydrogenation of aromatic ketones, methylene compounds are rapidly
Received October 17, 2007.
Address correspondence to Changjin Zhu, Department of Applied Chemistry,
Beijing Institute of Technology, No. 5 Zhongguancun South Street, Beijing
100081, China. E-mail: zcj@bit.edu.cn
2889

2890
R. Du et al.
Scheme 1. Preparation of aromatic aminoketones.
formed as final products via the intermediate benzyl alcohols, which are
difficult to obtain selectively. Hattori and coworkers have developed a
heterogeneous Pd-ethylenediamine [Pd=C(en)] complex catalyst in which
the diamine acts as a mild catalyst poison and succeeded in the pro-
duction of the benzyl alcohols from aromatic ketones.[6,7]
We investigated the transformation of aromatic amino ketones cata-
lyzed by commercial Pd=C and found that the formation of product in
the hydrogenation was dependent on the amino groups present in the
ketones.
RESULTS AND DISCUSSION
As the substrates of the hydrogenation catalyzed by Pd=C, aromatic
aminoketones were prepared as shown in Scheme 1. Mannich reaction
of acetophenones with paraformaldehyde and dimethylamine yielded
two typical Mannich bases, 1 and 2, which reacted with aniline and
ethylamine to give N-phenylamino-propiophenone (3), N-phenylamino-
p-nitropropiophenone (4), and N-ethylamino-propiophenone (6), respec-
tively. Compound 4 was reduced under hydrogen atmosphere by the Pd=C
catalysis to provide N-phenylamino-p-aminopropiophenone (5).
Initially, hydrogenation of ketones 1, 3, 5, and 6 was investigated using
a catalytic amount of commercial Pd=C in MeOH under hydrogen atmos-
phere for 1 day (Scheme 2 and Table 1). Compounds 3 and 5 were con-
verted into the corresponding reductive products of benzyl alcohols 8
and 10, respectively, without formation of fully hydrogenolyzed methylene
Scheme 2. Pd/C catalyzed hydrogenation of aromatic aminoketones.

2891

2892

Selective Hydrogenation of Ketones by Pd/C Catalysis
2893
compound. Both reactions were clean, and no chromatographic separation
was needed to obtain spectrally pure products. They gave excellent yields
of 83% for product 8 and 75% for 10. However, hydrogenation of 1 gave
only methylene product (compound 7 in Table 1) in 90% yield, and no
reaction was observed for 6. Comparison of the structures of ketone sub-
strates and their Pd=C-catalyzed hydrogenation results to each other sug-
gests that the primary and secondary aromatic amino groups in ketone 5
and the secondary aromatic amino group in 3 tempered Pd=C catalyst
and consequently led to the formation of alcoholic products 10 and 8,
whereas only the tertiary N,N-dimethylamino group in ketone 1 could
not temper Pd=C catalyst and therefore led to the formation of completely
reduced methylene product 7. The inactivation of Pd=C catalyst in the
reaction of 6 indicated that the aliphatic N-ethylamino group in 6 was
more harmful to the catalyst than the aromatic N-phenylamino group in 3.
We further retested the catalytic hydrogenation of ketones 1, 3, 5,
and 6 in a much longer reaction time of 7 days (Table 1). TLC (thin-layer
chromatography) analysis showed that 1 and 5 were fully converted to
methylene product 7 (88% yield) and alcohol 10 (79% yield), respect-
ively. Still no reaction was detected for 6 yet, indicating the strong inhi-
bition of Pd=C catalysis by the secondary aliphatic amino group. The
results were identical to those of reactions continued for 1 day. However,
only 3 showed a different hydrogenation result, which was transformed
almost equally into two products, alcohol 8 (20% yield) and methylene
product 9 (15% yield). Obviously, the Pd=C catalyzed reduction of 3 gave
the alcohol only during the reaction time of 1 day, and part of the pro-
duced alcohol was subsequently transformed to the further reduced
methylene product in a longer reaction time. It appears that Pd=C cata-
lyst was tempered by a single aromatic amino group in substrates and
further by two aromatic amino groups, and this led to the catalytic trans-
formation of aromatic ketones to alcohols chemoselectively. Although
direct evidence for the mechanism of catalytic poisonous effect toward
Pd=C by the amines has not been found, we suggest that the secondary
amino group might coordinate more tightly with palladium metal than
the tertiary one, and the aliphatic amino group more than the aromatic
one, because of their lesser steric hindrance. It has been reported that
ethylenediamine could coordinate with palladium metal and act as a mild
catalyst poison.[6]
In addition, ketone 4 containing a nitro group was reduced to the
double amino-containing ketone 5 in 91% yield (Scheme 1) without the
formation of further reduced product 10 during the reaction time of
1 h, indicating that the reduction of the nitro aminoketone 5 could occur
chemoselectively, in which the nitro group prior to carbonyl group was
hydrogenated by Pd=C catalysis. However, it strongly depended on the

2894
R. Du et al.
reaction time. The longer reaction time resulted in the further reduced
product of benzyl alcohol 10.
EXPERIMENTAL
General
1H NMR and 13C NMR spectra were recorded at 400 MHz (Varian
Mercury-Plus 400) and on a JEOL AL-300 spectrometer. Chemical shifts
(d) are quoted in parts per million (ppm) and coupling constants (J) are
given in hertz. Electrospray ionization mass spectra (ESI-MS) were
acquired using a Bruker Esquire 3000 ion trap spectrometer equipped with
a gas nebulizer probe. Gas chromatography mass spectrometry (GC-MS)
experiments were performed on a TraceGC 2000 gas chromatograph and a
Trace GC 2000 selective detector. Analytical thin-layer chromatography
(TLC) was performed on Merck silica gel-precoated plates. Pd=C (10%)
was purchased from Aldrich. Ketone substrates N-dimethylaminopropio-
phenone (1), N-dimethylamino-p-nitropropiophenone (2), N-phenyla-
mino-propiophenone (3), N-phenylamino-p-nitropropiophenone (4), and
N-ethylamino-propiophenone (6) were prepared as follow.[8,9]
N-Dimethylamino-p-nitropropiophenone Hydrochloride (2)
A solution of dimethylamine hydrochloride (0.82 g, 10 mmol), parafor-
maldehyde (0.45 g, 15 mmol), p-nitroacetophenone (1.65 g, 10 mmol),
and a few drops of hydrochloride in 30 ml of ethanol was refluxed for
5 h. Then an extra 1.5 g of paraformaldehyde (5 mmol) was added, and
the solution was refluxed further for 5 h. The resulting solution was
concentrated in vacuo, and 30 ml of water were poured onto the
residue. Then ethyl acetate was added for the extraction of unreacted
p-nitroacetophenone. Evaporation of the water layer and recrystalliza-
tion of the residue from ethanol gave a yellow solid of 0.9 g (35% yield).
ꢀ
1
Mp 187–188 C; H NMR (300 MHz, CDCl3) d 2.9 (s, 6H), 3.5 (m, 2H),
3.9 (t, 2H, J ¼ 18.4 Hz), 8.2 (m, 2H), 8.3 (t, 2H, J ¼ 17.4 Hz).
Substrate 1 was prepared in the same way.
N-Phenylamino-p-nitropropiophenone Hydrochloride (4)
Aniline (0.194 g, 2 mmol) and a few drops of hydrochloride were added
to a solution of 2 (0.258 g, 1 mmol) in 30 ml of 50% ethanol. Then the
mixture was refluxed for 4 h. A yellow solid was gradually precipitated

Selective Hydrogenation of Ketones by Pd/C Catalysis
2895
during the reaction. The resulting mixture was cooled to room
temperature. The precipitated solid was collected by fiꢀltration, and
1
0.275 g of product was obtained (90% yield). Mp 128–130 C; H NMR
(300 MHz, CDCl3) d 3.39 (t, 2H, J ¼ 8.4 Hz), 3.63 (t, 2H, J ¼ 8.4 Hz),
6.87 (d, 2H, J ¼ 5.4 Hz), 7.20 (m, 3H), 7.98 (d, 2H, J ¼ 9.6 Hz), 8.21
(d, 2H, J ¼ 9.6 Hz).
Substrate 3 was prepared in the same way.
N-Ethylamino-propiophenone (6)
Ethylamine (65–70% aqueous solution, 2 mmol) and a few drops of
hydrochloride were added to a solution of 1 (0.177 g, 1 mmol) in 30 ml
of 50% ethanol. Then the mixture was refluxed for 10 h. The resulting
mixture was first concentrated in vacuo and then chromatographed to
1
afford 0.075 g of product (42% yield). H NMR (400 MHz, CDCl3) d
1.1 (m, 3H), 2.5 (m, 2H), 3.2 (t, 2H, J ¼ 2.4 Hz), 3.8 (m, 2H), 7.4 (m,
2H), 7.9 (m, 3H). IR (KBr r=cmꢁ1): 1681.
General Procedure for the Preparation of 7–10 from the
Hydrogenation of 1, 3, 5, and 6
Pd=C (10% weight of the substrate) was added to a solution of a ketone
substrate (HCl salt, 0.5 mmol) in MeOH (10 ml). The reaction mixtures
were stirred under a slight pressure of hydrogen atmosphere (balloon)
at room temperature. After the reaction for an assigned time, the result-
ing mixtures were filtered through a plug of Celite1. The filtrates were
concentrated in vacuo to obtain the corresponding reduced products.
Data
N,N-Dimethyl-3-phenylpropylamine hydrochloride (7).
1
The product 7 was afforded in 88% yield from 1. H NMR (400 MHz,
CDCl3) d 2.0 (m, 2H), 2.6 (t, 2H, J ¼ 1.8 Hz), 2.7 (s, 6H), 2.9 (m, 2H),
7.1 (m, 3H), 7.2 (m, 2H); ESI-MS (m=z) 164.0 ([M þ H]þ).
N-Phenyl-3-phenyl-3-hydroxypropylamine (8).
1
The product 8 was afforded in 20% yield from 3. H NMR (400 MHz,
CDCl3) d 2.0 (m, 2H), 2.9 (m, 2H), 3.4 (m, 1H), 4.8 (m, 1H), 6.7–7.4
(m, 10H); GC-MS (m=z) 227.1 ([M þ H]þ ).

2896
R. Du et al.
N-Phenyl-3-phenylpropylamine (9).
1
The product 9 was afforded in 15% yield from 3. H NMR (400 MHz,
DMSO-d6) d 1.7 (m, 4H), 3.9 (m, 2H), 5.4 (m, 2H), 6.8 (t, 2H,
J ¼ 1.8 Hz), 7.1–7.3 (m, 8H); GC-MS (m=z) 211.2 ([M þ H]þ ).
N-Phenyl-3-(4-amino)phenyl-3-hydroxypropylamine hydrochloride (10).
1
The product 10 was afforded in 75% yield from 5. H NMR (400 MHz,
CDCl3) d 2.1 (m, 2H), 3.2 (m, 2H), 3.4 (s, 3H), 4.8 (s, 1H), 6.6–6.7 (m,
5H), 7.2–7.3 (m, 4H); 13C NMR d 38.2, 41.9, 73.7, 113.4, 115.4, 117.8,
127.2, 129.5, 134.6, 146.2, 148.6.
No reaction was detected for ketone substrate 6.
ACKNOWLEDGMENTS
This study was supported by National Natural Science Foundation of
China (No. 20372009).
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Selective Hydrogenation of Ketones by Pd/C Catalysis
2897
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