Direct one-pot reductive amination of aldehydes with nitroarenes in a domino fashion: Catalysis by gum-acacia-stabilized palladium nanoparticles

Article abstract of DOI:10.1021/jo901787t

(Figure Presented) This note describes the direct reductive amination of carbonyl compounds with nitroarenes using gum acacia-palladiumnanoparticles, employing molecular hydrogenas the reductant. This methodology is found to be applicable to both aliphatic and aromatic aldehydes and a wide range of nitroarenes. The operational simplicity and the mild reaction conditions add to the value of this method as a practical alternative to the reductive amination of carbonyl compounds.

Full text of DOI:10.1021/jo901787t

pubs.acs.org/joc
those of polysaccharides, to create high-performance and en-
Direct One-Pot Reductive Amination of Aldehydes
with Nitroarenes in a Domino Fashion: Catalysis by
Gum-Acacia-Stabilized Palladium Nanoparticles
vironmentally friendly catalysts that are chemically stable but
biodegradable. Gum acacia (GA) is a highly branched, neutral
or slightly acidic arabinogalactan polysaccharide, obtained
naturally from the stems and branches of the Acacia Senegal
tree. Nontoxic and biocompatible properties of GA made it
widely used in food and pharmaceutical industry as an additive
or emulsifying agent. Moreover, it is also being increasingly
B. Sreedhar,* P. Surendra Reddy, and D. Keerthi Devi
Indian Institute of Chemical Technology, Council of Scientific
and Industrial Research, Hyderabad-500007, India
5
used as a stabilizer for various novel nanomaterials.
Recently, we have reported the reduction and stabilization of
silver nanoparticles at room temperature using naturally occur-
sreedharb@iict.res.in
6
ring GA. Continuing pursuit in the synthesis of nanoparticles,
Received August 18, 2009
we have developed an efficient straightforward approach for
the aqueous-phase synthesis of Pd nanoparticles (9 ( 1 nm)
using gum acacia as both a reducing and stabilizing agent.
Sequential transition metal catalysis is a conceptually
challenging field of research and has recently aroused con-
7
siderable interest. Most remarkably, without further cata-
lyst addition a particular metal readily shifts gears to catalyze
further transformations either in a parallel or in a sequential
8
fashion. Additionally, one-pot transformations are econo-
mically and ecologically highly intriguing for developing
efficient new synthetic processes in a domino fashion, gene-
This note describes the direct reductive amination of
carbonyl compounds with nitroarenes using gum acacia-
palladium nanoparticles, employing molecularhydrogenas
the reductant. This methodology is found to be applicable
to both aliphatic and aromatic aldehydes and a wide range
of nitroarenes. The operational simplicity and the mild
reaction conditions add to the value of this method as a
practical alternative to the reductive amination of carbonyl
compounds.
9
rating a suitable reactive functionality en route. The reduc-
tive amination reaction remains one of the most powerful
and widely utilized transformations that allow the direct
conversion of carbonyl compounds into amines using simple
10
operations. The reaction offers compelling advantages
over other amine syntheses, including brevity, wide com-
mercial availability of substrates, generally mild reaction
conditions, and no need to isolate the imine intermediate.
The resulting amines and their derivatives are highly versatile
building blocks for various organic substrates and are essen-
tial precursors to a variety of biologically active compounds,
1
1
such as pharmaceuticals and agrochemicals.
Metal nanoparticles are attractive for catalysis because of
their large surface area-to-volume ratio, which allows the
(5) Bandyopadhyaya, R.; Nativ-Roth, E.; Regev, O.; Yerushalmi- Rozen,
1
effective utilization of expensive metals. Palladium nano-
R. Nano Lett. 2002, 2, 25. (b) Kattumuri, V.; Katti, K.; Bhaskaran, S.; Boote,
E. J.; Casteel, S. W.; Fent, G. M.; Robertson, D. J.; Chandrasekhar, M.;
Kannan, R.; Katti, K. V. Small 2007, 3, 333. (c) Velikov, K. P.; Zegers, G. E.;
van Blaaderen, A. Langmuir 2003, 19, 1384.
particles, particularly with dimension less than 10 nm,
exhibit unexpectedly high catalytic activities toward differ-
ent types of reactions, a property not revealed in bulk
(
6) Mohan, Y. M.; Raju, K. M.; Sambasivudu, K.; Singh, S.; Sreedhar, B.
J. Appl. Polym. Sci. 2007, 106, 3375.
7) For recent reviews, see: (a) Ajamian, A.; Gleason, J. L. Angew. Chem.
2004, 116, 3842. (b) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. Rev.
004, 33, 302.
2
palladium. Unfortunately, however, aggregation of naked
3
nanoparticles often prohibits tailoring of particle size. To
(
2
overcome this problem, palladium nanoparticles are gener-
ally dispersed on support materials, among which polymers
(
(
8) Braun, R. U.; M u€ ller, T. J. J. Mol. Diversity 2003, 6, 251.
9) For recent reviews on transition-metal-assisted sequential transfor-
4
are commonly used. There is considerable interest in ex-
ploiting natural polymer macrostructures, and in particular
mations and domino processes, see: (a) Balme, G.; Bossharth, E.; Monteiro,
N. Eur. J. Org. Chem. 2003, 4101. (b) Battistuzzi, G.; Cacchi, S.; Fabrizi, G.
Eur. J. Org. Chem. 2002, 2671. (c) Negishi, E. I.; Coperet, C.; Ma, S.; Liou, S.
Y.; Liu, F. Chem. Rev. 1996, 96, 365. (d) Tietze, L. F. Chem. Rev. 1996, 96,
115.
(
1) (a) Fendler, J. H. Nanoparticles and Nanostructured Films: Preparation,
Characterization and Applications; Wiley-VCH: Weinhein, Germany, 1998. (b)
Schmid, G. In Nanoscale Materials in Chemistry; Klabunde, K. J., Ed.; Wiley-
Interscience: New York, 2001; pp 15-59.
(10) (a) Baxter, E. W.; Reitz, A. B. Org. React. 2002, 59, 1. (b) Hutchins,
R. O.; Natale, N. R. Org. Prep. Proced. Int. 1979, 11, 201. (c) Lane, F.
Synthesis 1975, 135. (d) For reviews on reductive amination, see: Hutchins, R.
O.; Hutchins, M. K. Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 8, p 25. Baxter, E. W.; Reitz, A. B. Organic
Reactions; Wiley: New York, NY, 2002; Vol. 59, p 1. Hudlicky, M. Reductions in
Organic Chemistry, 2nd ed.; ACS Monograph 188; American Chemical Society:
Washington, DC, 1996; p 187.
(
2) (a) Kobayashi, H.; Yamauchi, M.; Kitagawa, H.; Kubota, Y.; Kato,
K.; Takata, M. J. Am. Chem. Soc. 2008, 130, 1828. (b) Jansat, S.; Gomez, M.;
Philippot, K.; Muller, G.; Guiu, E.; Claver, C.; Castillon, S.; Chaudret, B. J.
Am. Chem. Soc. 2004, 126, 1593. (c) Kidambi, S.; Dai, J.; Li, J.; Bruening, M.
L. J. Am. Chem. Soc. 2004, 126, 2658.
(
(
3) Zhao, M.; Sun, L.; Crooks, R. M. J. Am. Chem. Soc. 1998, 120, 4877.
4) (a) Gao, H.; Xu, Y.; Liao, S.; Yu, D. React. Polym. 1994, 23, 113. (b)
(11) (a) Merla, B.; Risch, N. Synthesis 2002, 1365. (b) Gordon, E. M.;
Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem.
1994, 37, 1385. (c) Sharp, D. B. In Herbicides: Chemistry, Degradation, and
Mode of Action; Kearney, P. C., Kaufman, D. D., Eds.; Marcel Dekker: New York,
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Gallezot, P.; Laurain, N.; Isnard, P. Appl. Catal., B 1996, 9, 11. (c) Wall, V.
M.; Eisenstadt, A.; Ager, D. J.; Laneman, S. A. Platinum Met. Rev. 1999, 43,
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1
8
806 J. Org. Chem. 2009, 74, 8806–8809
Published on Web 10/20/2009
DOI: 10.1021/jo901787t
r 2009 American Chemical Society

Sreedhar et al.
JOCNote
Several reagents that effect reductive amination have been
recently developed, including the following: catalytic hydro-
ion intermediately upon reaction of a carbonyl compound
with amine, followed by in situ reduction to an alkylated
amine of higher order in a single operation.
1
2
13
14
genation, Zn-AcOH, Et SiH-CF CO H, Bu SnH-
3
3
2
3
1
5
16
DMF, InCl -Et SiH, triazole-derived iridium(I) carbine
The palladium nanoparticles immobilized in GA were
prepared by the reaction of PdCl with GA in water at
3
3
1
complexes, [Ir(cod) ]BF , Rh(I) catalysts, and various
7
18
19
2
4
2
2
0
modified borohydride derivatives. However, in terms of
functional group tolerance, side reactions, and reaction
conditions, most of these reagents may have one or more
drawbacks. Moreover, since carbonyl compounds them-
selves are also reduced under the conditions used, many of
these reactions require an excess amount of the amines to
obtain good yields of products. As a result, the choice of
reducing agent is very critical to the success of the reaction,
since the reducing agent must reduce imines selectively over
aldehydes.
100 °C for 6 h, without using any reducing or stabilizing
agent. The palladium nanoparticles stabilized with GA were
separated by adding acetone to the reaction mixture. Since
GA around the nanoparticles is not soluble in most organic
solvents, it passivates the surface of the Pd nanoparticles and
suppresses the growth and agglomeration of the particles. It
also protects from oxidation, although hydrogen can pene-
24
trate through, similar to PVP-coated Pd nanoparticles. The
prepared catalyst was well characterized with XRD, TEM,
2
5
XPS, IR, UV-vis, and AAS. Figure 1 shows the TEM
images of Pd nanoparticles synthesized using gum acacia as
both reducing and stabilizing agent at 100 °C for 6 h. As can
be seen in the TEM images both in the fresh and used
catalysts the particle size is in the range of 9 ( 1 nm and
also clearly confirms no change in the morphology even after
five cycles.
Recently, attempts have been made to carryout reductive
amination of carbonyl compounds directly with nitroben-
zene for the preparation of N-alkylated aromatics. Yoon
et al. reported reduction of nitroaromatics using a decabor-
ane-Pd/C system followed by reductive amination with
2
1
carbonyls using decaborane. Rhee et al. reported on re-
ductive N-alkylation of anilines and nitroarenes with alde-
-
þ
22
hydes using HCOO NH /Pd/C. Although these methods
4
are encouraging, there is a considerable scope for improve-
ment. For example, Yoon’s method requires acetic acid to
prevent reductive etherification and high temperature, and
Rhee’s method is not applicable to aromatic aldehydes.
Clearly, the development of improved procedures in which
more sustainable catalysts and wide applications are used
has remained an elusive goal. More recently, Syndes et al.
reported reductive monoalkylation of nitroaryls in the
2
3
absence of any additives. To the best of our knowledge,
however, no palladium nanoparticles promoted reductive
N-alkylation of nitroarenes using molecular hydrogen as
reducing agent and in the absence of any additives has been
reported to date. In the present work, we report our inves-
tigations on the application of GA-Pd nanoparticles for the
practical and atom economic synthesis of mono N-alkyl
amines through reductive amination of aldehydes with
nitroarenes under the atmospheric pressure of hydrogen.
The overall process involves the reduction of nitro com-
pound to amine and the formation of an imine or iminium
FIGURE 1. TEM images and histograms showing the particle size
distribution of GA-Pd nanoparticles before (a) and after (b) cata-
lysis observed at 120 kV. Inset shows the selected area diffraction
patterns and images in enlarged scale.
(
(
12) T1arasevich, V. A.; Kozlov, N. G. Russ. Chem. Rev. 1999, 68, 55.
13) Micovic, I. V.; Ivanovic, M. D.; Piatak, D. M.; Bojic, V. D. Synthesis
SCHEME 1
1
991, 1043.
14) Chen, B.-C.; Sundeen, J. E.; Guo, P.; Bednarz, M. S.; Znao, R.
Tetrahedron Lett. 2001, 42, 1245.
(
(
(
15) Suwa, T.; Sugiyama, E.; Shibata, I.; Baba, A. Synthesis 2000, 6, 789.
16) Lee, O. Y.; Law, K. L.; Ho, C.; Yang, Y. D. J. Org. Chem. 2008, 73,
8
829.
17) Gnanamgari, D.; Moores, A.; Rajaseelan, E.; Crabtree, R. H.
Organometallics 2007, 26, 1226.
18) Imao, D.; Fujihara, S.; Yamamoto, T.; Ohta, T.; Ito, Y. Tetrahedron
005, 61, 6988.
19) Tararov, V. I.; Kadyrov, R.; Riermeierc, T. H.; Borner, A. Chem.
Commun. 2000, 1867.
20) (a) Lane, C. F. Synthesis 1975, 135. (b) Abdel-Magid, A. F.; Carson,
K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,
(
An initial evaluation of the proposed reductive amination
was performed with benzaldehyde and nitrobenzene, under
an atmospheric pressure of hydrogen at room temperature
in methanol using different palladium catalysts (Table 1).
Optimum yield of the product (88%) was obtained by using
GA-Pd(0) (entry 1). No product was formed when the
reaction was run in absence of the catalyst. When the
reaction was performed in the presence of Pd-SiO2 and
(
2
(
(
3
5
849. (c) Bomann, M. D.; Guch, I. C.; Dimare, M. J. Org. Chem. 1995, 60,
995. (d) Bhattacharyya, S. Synth. Commun. 1997, 4265. (e) Ranu, B. C.;
Majee, A.; Sarkar, A. J. Org. Chem. 1998, 63, 370. (f) Bhattacharyya, S.;
Neidigh, K. A.; Avery, M. A.; Williamson, J. C. Synlett 1999, 1781. (g)
Saxena, I.; Borah, R.; Sarma, J. C. J. Chem. Soc., Perkin Trans.1 2000, 503.
Pd-TiO , the nitrobenzene was reduced to the correspon-
2
ding amine moderately, but the hydrogenation of in situ
(
21) Bae, J. W.; Cho, Y. J.; Lee, S. H.; Yoon, C. O. M.; Yoon, C. M.
Chem. Commun. 2000, 1857.
22) Byun, E.; Hong, B.; De Castro, K. A.; Lim, M.; Rhee, H. J. Org.
Chem. 2007, 72, 9815.
23) Sydnes, M. O.; Kuse, M.; Isobe, M. Tetrahedron 2008, 64, 6406.
(
(24) Yamaguchi, M.; Kitagawa, H. Synth. Met. 2005, 153, 353.
(25) Catalyst characterization data given in Supporting Information.
(
J. Org. Chem. Vol. 74, No. 22, 2009 8807

Sreedhar et al.
JOCNote
TABLE 1. Comparative Study of Different Supported Palladium Cat-
alyst for Reductive Amination
TABLE 3. GA-Pd Nanoparticles Catalyzed Reductive Amination of
Different Aldehydes with Nitrobenzene under H Atmosphere
2
a
a
b
entry
catalyst
time (h)
yield (%)
1
2
3
4
a
GA-Pd
Pd-TiO
6
24
24
6
88
0
0
20
2
Pd-SiO
Pd-C
2
Reaction conditions: benzaldehyde (1 mmol) nitrobenzene (1.2
mmol), catalyst (1.3 mol %), and methanol (5 mL) at room temperature
2
under H atmosphere for 6 h.
generated imine did not proceed even at elevated tempera-
tures (entries 2 and 3). Commercially available 10% Pd/C
also failed to form any perceptible amount of the product in
the hydrogenation of imine intermediate, although a good
amount of amine was formed from the nitrobenzene under
our reactions conditions (entry 4). The enhanced activity of
GA-Pd catalyst over other supported palladium catalysts
screened results from the high surface area and strong
hydrogen-trapping property of palladium nanoparticles
2
a
compared to bulk palladium.
The heterogeneity of the catalyst is also evaluated to study
whether the reaction using solid Pd catalysts occurred on the
solid surface or was catalyzed by Pd species in the liquid
phase. To address this issue, we conducted two separate
experiments with benzaldehyde and nitrobenzene. In the first
experiment, the reaction was terminated after 1 h, and the
conversion of nitrobenzene was found to be 31%. At this
juncture, the catalyst was separated from the reaction mix-
ture and the reaction was continued with the filtrate for an
additional 5 h. In the second experiment, the reaction was
terminated after 2 h at 55% conversion, and the catalyst was
removed. The reaction was continued with the filtrate for an
additional 5 h. In both the cases, the conversion remained
almost unchanged. Pd was not detected in the filtrate in
either experiment by ICP-AES. These studies demonstrate
that only the Pd bound to acacia during the reaction is active
and the reaction proceeds on the heterogeneous surface.
As can be seen from Table 2, for both aliphatic and
aromatic aldehydes, GA-Pd catalyst is recyclable and can
be recovered by simple filtration in air and reused without
significant loss of catalytic activity (Table 2).
a
Reaction conditions: aldehyde (1 mmol), nitrobenzene (1.2 mmol),
methanol (5 mL), and Pd catalyst (1.3 mol %) at room temperature.
aldehydes regardless of whether they are linear or R-
branched underwent the reductive amination rapidly and
gave the products in excellent yield without any byproducts
(
Table 3, entries 7-10).
Similarly, terephthaldicarboxaldehyde also underwent
reductive amination smoothly to give the corresponding
product in good yield (Scheme 2).
SCHEME 2
TABLE 2. Reductive Amination of Aldehydes with Nitrobenzene over
Five Cycles
a
cycle (% yield)
entry aldehyde first second third fourth fifth average % yield
1
2
C
C
3
6
H
H
7
-CHO 92
-CHO 88
90
87
89
84
90
84
87
81
90
85
6
a
Reaction conditions: aldehyde (1 mmol), nitrobenzene (1.2 mmol),
and Pd catalyst (1.3 mol %) at room temperature for 6 h under 1 atm of
hydrogen.
Aliphatic aldehydes gave excellent yield of the desired
products because the imine intermediate formed is unstable
and is readily converted to the product by hydrogenation. On
the other hand, in case of aromatic aldehydes, though the
imine intermediate formed is stable, it undergoes backward
reaction to form aldehyde and amine, resulting in a competi-
tion between hydrogenation and backward reaction that
leads to a decrease in yield.
In light of these excellent results various nitroarenes were
subjected to the reductive amination with benzaldehyde
to explore the scope of nitro substrates (Table 4). Unsubsti-
tuted (Table 3) as well as substituted 4-methyl, 4-fluoro,
4-methoxy, 2-methoxy, 2-methyl, 4-hydroxy nitrobenzenes
Under the optimized reaction conditions, the scope of the
reaction was explored with structurally and electronically
diverse aldehydes with a wide range of nitroarenes. As
revealed in Table 3, various aldehydes were reductively
aminated with nitrobenzene under ambient pressure of
molecular hydrogen. The aldehydes used for this study
included aromatic and aliphatic examples. Irrespective of
the electronic nature of the substituent, aromatic aldehydes
reacted smoothly to give the corresponding products in good
yields (Table 3, entries 1-6). On the other hand, aliphatic
8
808 J. Org. Chem. Vol. 74, No. 22, 2009

Sreedhar et al.
JOCNote
TABLE 4. GA-Pd Nanoparticles Catalyzed Reductive Amination of
Benzaldehyde with Different Nitroarenes under H Atmosphere
2
SCHEME 3
a
that combines the catalytic power of transition-metal com-
plexes with the architecture of polysaccharides under ambi-
ent pressure of hydrogen. This protocol can be used to
generate a diverse range of N-alkyl amines in good to
excellent yields. The simple procedure for catalyst prepara-
tion, easy recovery, and reusability of the catalyst is expected
to contribute to its utilization for the development of benign
chemical processes and products.
Experimental Section
Typical Experimental Procedure for the Reductive Amination
of Aldehydes with Nitroarenes. The catalyst GA-Pd (100 mg,
1
.3 mol %) was suspended in methanol (3 mL), and a hydrogen
balloon was fitted to the flask. The suspended catalyst was
stirred under hydrogen atmosphere for 20 min at room tem-
perature, and then a solution of the nitroarene (1.2 mmol) and
aldehyde (1 mmol) dissolved in methanol (2 mL) was added to it.
The resultant solution was stirred under hydrogen atmosphere
at room temperature for the specified period. The progress of the
reaction was monitored by TLC. The reaction mixture was
filtered, and the solvent was removed under reduced pressure
to give the crude product. It was purified by column chromato-
graphy on silica gel using hexane-ethyl acetate mixture as
eluent.
a
Reaction conditions: benzaldehyde (1 mmol), nitroarene (1.2 mmol),
methanol (5 mL), and Pd catalyst (1.3 mol %) at room temperature.
gave the desired product in comparable yields. However, for
4
-hydroxy nitrobenzene though TLC showed complete con-
version, isolation of the final product by column chroma-
tography gave the product in only 76% yield. It was observed
that in all of these reactions there was no formation of any
side products.
Apart from the reductive amination of aldehydes with
nitrobenzene, we are also interested in similar reactions of
other carbonyl compounds. Some preliminary experiments
demonstrate the feasibility of our method for the reductive
amination of acetophenone with nitrobenzene at 80 °C
temperature as shown in Scheme 3. The result is, however,
interesting because acetophenone has shown to be an inert or
a difficult substrate in some reported reductive amination
Benzyl-phenyl-amine (Table 3, entry 1). IR (neat): 3418, 2923,
735, 1601, 1505, 1252, 1069, 749 cm . H NMR (300 MHz,
-1
1
1
CDCl ): δ 3.93 (brs, 1H), 4.31 (brs, 2H), 6.56 (d, 2H, J =
3
7.8 Hz), 6.65 (t, 1H, J = 7.2 Hz), 7.11 (d, 2H, J = 7.5 Hz), 7.21 -
1
3
7.35 (m, 5H). C NMR (75 MHz, CDCl ): δ 48.26, 112.70,
3
117.5, 127.2, 127.4, 128.6, 129.2, 139.4, 148. ESI MS (m/z): 184
M þ H).
(
Reuse of Catalyst. After completion of the reaction the
catalyst was recovered by filtration and washed several times
with ethyl acetate and then ether and dried for further reuse. The
catalyst showed consistent activity for five cycles.
Acknowledgment. P.S.R. thanks the Council of Scientific
and Industrial Research, New Delhi for the award of Senior
Research Fellowship.
2
6
reactions.
In conclusion, we have developed a simple and efficient
method for the synthesis of N-alkyl amines via reductive
amination using a new readily recoverable hybrid catalyst
Supporting Information Available: General experimental
procedures, catalyst preparation and characterization data of
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
26) (a) Abdel-Magid, A. F.;Carson,K. G.;Harris, B. D.;Maryanoff,C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849. (b) Cho, B. T.; Kang, S. K.
Tetrahedron 2005, 61, 5725. (c) Apodaca, R.; Xiao, W. Org. Lett. 2001, 3, 1745.
J. Org. Chem. Vol. 74, No. 22, 2009 8809