Reductive amination of carbonyl compounds over silica supported palladium exchanged molybdophosphoric acid catalysts

Article abstract of DOI:10.1007/s10562-012-0778-4

Palladium exchanged molybdophosphoric acid supported on silica is reported as a highly effective catalyst for direct reductive amination of carbonyl compounds. The catalysts are characterized by X-ray diffraction and FT-infrared spectroscopy. The characterization results support the existence of Keggin ion of heteropoly molybdate on silica. The catalyst is facile, water tolerable and environmentally benign for reductive amination. A variety of secondary and tertiary amines can be synthesized over this catalyst in excellent yields under mild reaction conditions. A plausible reaction mechanism is proposed for the reductive amination of carbonyl compounds over this catalyst.

Full text of DOI:10.1007/s10562-012-0778-4

Catal Lett (2012) 142:389–396
DOI 10.1007/s10562-012-0778-4
Reductive Amination of Carbonyl Compounds over Silica
Supported Palladium Exchanged Molybdophosphoric Acid
Catalysts
•
A. Srivani P. S. Sai Prasad N. Lingaiah
•
Received: 12 July 2011 / Accepted: 28 January 2012 / Published online: 17 February 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Palladium exchanged molybdophosphoric acid
supported on silica is reported as a highly effective catalyst
for direct reductive amination of carbonyl compounds.
The catalysts are characterized by X-ray diffraction and
FT-infrared spectroscopy. The characterization results
support the existence of Keggin ion of heteropoly molyb-
date on silica. The catalyst is facile, water tolerable and
environmentally benign for reductive amination. A variety
of secondary and tertiary amines can be synthesized over
this catalyst in excellent yields under mild reaction con-
ditions. A plausible reaction mechanism is proposed for the
reductive amination of carbonyl compounds over this
catalyst.
synthesis of structurally diverse primary, secondary and
tertiary amines [4, 5]. Amines and their derivatives are
highly versatile building blocks for various organic sub-
strates and are essential starting materials for variety of
biological active compounds. Amines and their derivatives
are widespread among natural products such as alkaloids,
amino acids, nucleic acids [6–12].
Two synthetic methods are commonly used for reduc-
tive amination. One is the direct reductive amination, in
which a mixture of carbonyl compound and amine are
treated directly with suitable reducing agents in a single
operation without formation of an intermediate imine or
iminium salt. The other one is a stepwise or indirect
reaction, in which the first step is the conversion of amine
into imine and further reduction of imine reduced into
higher alkylated amine. In indirect reductive amination
method the imine derivative can be isolated from the
reaction mixture [2, 8, 13].
Keywords Carbonyl compounds Á Amines Á Reductive
amination Á Palladium Á Molybdophosphoric acid
1 Introduction
The direct reductive amination of aldehydes and ketones
is used extensively compared to indirect method to prepare
primary, secondary, and tertiary amines. Direct reductive
amination is performed under anhydrous conditions in
order to avoid decomposition of the reducing agents or
catalysts, and at the same time to enhance the generation of
the intermediate imines or iminiun salts.
Reductive amination of carbonyl compounds, or reductive
alkylation of amines, where the reaction of amines with
aldehydes and ketones in the presence of a reducing agent
is one of the widely used and fundamental reaction in
organic synthesis [1–3]. In this reductive amination the
overall process involves the formation of an imine or
iminium intermediate followed by reduction to alkylated
amines. Reductive amination of carbonyl compound is a
very important and powerful tool for chemists to target the
There are several reagents and catalysts reported in the
literature for reductive amination, following direct as well
as indirect approaches [14–17]. In most of these methods
are used acid catalyst/reagent along with a reducing agent
like NaBH4. Pd and In based homogeneous catalysts are
reported for the direct reductive amination [6, 11, 18, 19].
Most of these methods have some drawbacks in one way or
another such as excess amount of reagents, acidic condi-
tions, higher reaction temperature, prolonged reaction
time, inert conditions and toxic by-products. Recently
A. Srivani Á P. S. S. Prasad Á N. Lingaiah (&)
Catalysis Laboratory, Inorganic and Physical Chemistry
Division, Indian Institute of Chemical Technology,
Hyderabad 500 607, India
e-mail: nakkalingaiah@iict.res.in
123

390
A. Srivani et al.
Table 1 Comparison of catalysts for reductive amination of benz-
aldehyde with aniline
20PdMPA/SiO (used)
2
Catalyst
Imine
Amine
Alcohol
yielda (%) yielda (%) yielda (%)
20MPA/SiO
2
20% PdMPA/SiO2
20% CuMPA/SiO2
20% MPA/SiO2
0.8
86.5
79.4
93
0.5
–
1.2
–
–
20PdMPA/SiO
2
20% CuMPA/SiO2 (reduced) 54.5
–
–
PdMPA
2% Pd/SiO2
Blank
7.0
6.3
63
73
–
12
20
–
38
Reaction conditions: benzaldehyde (1 mmol); aniline (1 mmol); cat-
alyst weight (50 mg); solvent 3 ml; reaction temperature: 60 °C,
reaction time: 30 min H2 atmosphere
2200 2000 1800 1600 1400 1200 1000 800
600
400
a
Yields were determined by GC–MS analysis
Wave number (cm-1)
Fig. 1 FT-IR Spectra of silica supported palladium exchanged
molybdophosphoric acid and silica supported molybdophosphoric
acid catalysts
simple and environmentally benign conditions for all three
types of amines.
Heteropoly acids (HPAs) particularly Keggin types are
known as better acid and oxidation catalysts. HPAs are
noncorrosive and environmentally benign catalysts used for
different organic transformations both in homogenous and
heterogeneous conditions [21]. HPA has been attained much
attention due to their unique properties such as well-defined
structure, Bronsted acidity and possibility to modify their
acid–base properties. These catalysts have the ability to
accept and release electrons and possess high proton
mobility [22]. In continuation of our interest for the appli-
cation of heteropolyacids as environmentally benign cata-
lysts for various organic transformations [23, 24], we report a
heterogeneous palladium exchanged molybdophosphoric
acid (MPA) supported on silica catalyst for the reductive
amination of aldehydes and ketones. Most of the reductive
amination catalysts are water sensitive and non selective
[16]. The advantage of the present catalyst is that it is not
water sensitive and also selective for monoalkylation.
PdMPA
5
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
2 Theta (°)
20% PdMPA/SiO2
10
20
30
40
50
60
70
80
2 Theta (°)
2 Experimental
Fig. 2 XRD patterns of silica supported palladium exchanged
molybdophosphoric acid and bulk palladium exchanged molybdo-
phosphoric acid catalysts
2.1 Catalyst Preparation
heterogeneous gold (I), Pt, Pd catalysts supported on dif-
ferent acid and base supports are used for reductive ami-
nation reaction [20]. These catalysts have advantages over
homogenous catalysts. However, reported conversions are
low and require long reaction time and high temperature.
Though many of the reported protocols for reductive
amination reaction work well for the preparation of tertiary
amines and synthesis of secondary amines is compromised
by over alkylation in many cases [7, 14–17]. Thus, it is
necessary to develop an alternative method that employs
The palladium containing MPA catalyst was prepared by
exchanging the protons of 12-MPA in stepwise. Initially
0.281 g of barium hydroxide was added to the aqueous
solution containing 2.0 g of MPA to exchange its protons
with Ba. Later aqueous solution containing 0.20 g of
PdSO4 was added slowly while stirring to replace Ba with
Pd by eliminating Ba as BaSO4. Thus the Pd exchanged
MPA (PdMPA) was recovered from the solution by
recrystallization [25]. The Pd containing MPA on silica
was prepared by wet impregnation method. The required
123

Reductive Amination of Carbonyl Compounds
391
NH2
CHO
20% PdMPA/SiO2
H2
N
CH
NH CH2
Scheme 1 Reaction pathway for the reductive amination of carbonyl compounds
25 ml two-necked round bottom flask. About 50 mg of
catalyst was added to the reaction mixture and stirred at
60 °C on oil bath under hydrogen at atmospheric atmo-
sphere. The progress of the reaction was monitored by
using thin layer chromatography. The products were
identified by GC–MS (SHIMADZU-2010) analysis by
separating the products on a DB-5 column.
Table 2 Reductive amination in presence of different solvents
Solvent
Yielda (%)
Imine
Amine
Benzyl alcohol
H2O
34.7
3.0
55.7
74.6
53.0
64.0
46.2
93.0
67.0
2.7
1.8
2.1
2.5
1.0
1.2
3.0
EtOH
MeOH
2.1
Isopropanol
1,4-dioxane
DMF
13.5
31.5
0.8
3 Results and Discussion
Toluene
8.0
The FTIR spectra of the catalysts are presented in Fig. 1.
The 20% PdMPA/SiO2 and 20% MPA/SiO2 catalysts
showed similar IR patterns. The IR bands were observed at
1,093, 961, 861 and 789 cm-1, attributed to characteristic
Keggin ion stretching vibrations of P–Od, Mo=Ot, Mo–Ob–
Mo and Mo–Oc–Mo respectively [26]. This indicates that
during the exchange of Pd with protons of MPA the Keggin
ion structure is intact and the Keggin structure is present on
the support.
Reaction conditions: benzaldehyde (1 mmol); aniline (1 mmol); cat-
alyst weight (50 mg); reaction temperature: 60 °C, reaction time:
30 min H2 atmosphere
a
Yields were determined by GC–MS analysis
amount of PdMPA (0.8 g) dissolved in distilled water
(10 ml) and added to silica (4 g). The catalyst mass was
dried on water bath and further dried at 120 °C for 12 h in
oven. Finally the catalyst was calcined at 300 °C for 2 h.
The amount of PdMPA on silica was 20 wt%. Similarly 20
wt% MPA supported on silica was also prepared in the
same procedure where MPA was taken instead of PdMPA.
The amount of Pd exchanged with the proton of MPA is
calculated by atomic absorption spectroscopy (AAS)
analysis. The protons present in MPA are partially
exchanged with Pd ion. Based on these results the PdMPA
is in the form of Pd2.8H0.2MPA. The Cu exchanged MPA
supported on silica was prepared with similar procedure as
described above by taking calculated amount of Cu (NO3)2
instead of PdSO4.
X-ray diffractogram of 20% PdMPA/SiO2 catalyst is
shown in Fig. 2 and the diffractogram of bulk PdMPA also
shown in the insert of the figure. The XRD patterns related
to Keggin ion structure are clearly seen for the bulk
PdMPA. The characteristic peaks at 2h values of 10.5°,
23.7°, 26.1°, 30.2° and 35.6° are assigned to Keggin
structure of MPA. When PdMPA is supported on silica the
catalyst showed broad XRD patterns. This suggests that the
Keggin ion of PdMPA was highly dispersed on silica. Even
though the Keggin patterns are not seen in XRD for the
supported catalysts, the existence of the Keggin structure
can be conformed from FT-IR and XRD of bulk PdMPA
analysis.
2.2 Characterization of Catalysts
Initially the reaction of benzaldehyde with aniline using
a series of silica supported heteropoly molybdate catalysts
was studied and the results are shown in Table 1. The
catalysts 20% MPA/SiO2 and 20% CuMPA/SiO2 yielded
mainly imine. The reduction of imine to amine is relatively
low over these catalysts. The 20% PdMPA/SiO2 catalyst
afforded about 93% yield to amine. This result indicates
that MPA and Cu containing MPA are able to catalyse the
formation of imine and further reduction to amine is very
low. Silica supported copper exchanged MPA catalyst after
was subjected to reduction to reduce Cu and studied for this
reaction. This catalyst also yielded only imine. This result
suggests that no further reduction took place with copper
ions and copper metal. The pre-reduced 2% Pd/SiO2
X-ray powder diffraction patterns were recorded on of
Rigaku Miniflex diffractometer using Cu Ka radiation
(1.5406 A8) at 40 kV and 30 mA and secondary graphite
monochromatic. The measurements were obtained in steps
of 0.045° with account time of 0.5 s and in the 2h range of
10–80°. The FT-IR spectrum was recorded on a Bio-rod
Excalibur series spectrometer using the KBr disc method.
2.3 General Reaction Procedure
In a typical reaction procedure a mixture of aldehyde
(1 mmol), aniline (1 mmol) and DMF (3 ml) were taken in
123

392
A. Srivani et al.
Table 3 Synthesis of substituted reductive amination products over 20% PdMPA/SiO2 catalyst
Imine yields a
Amine yields a
93.0
Amine
S.No
Aldehyde
Amine
CHO
NH2
NH2
N
H
2.2
1
2
CHO
75.7
N
H
1.8
2.8
H3CO
H3CO
CHO
CHO
CHO
CHO
NH2
NH2
N
H
81.5
91.8
78.6
3
4
CH3
CH3
N
H
3.7
F
F
NH2
NH2
11.9
5
6
N
H
Cl
Cl
N
H
66.9
44.8
18.3
17.0
Br
Br
CHO
NH2
N
H
7
NO2
HO
NO2
OH
NH2
NH2
CHO
CHO
N
H
55.3
63.0
7.5
8
9
10.1
N
H
Cl
F
Cl
CHO
NH2
NH2
NH2
54.0
22.7
N
H
10
F
NO2
CHO
CHO
N
H
11
12
40.5
0.35
10.5
88.5
NO2
N
H
123

Reductive Amination of Carbonyl Compounds
393
Table 3 continued
S.No
Imine yields a
Cabonyl compound
CHO
Amine yieldsa
Amine
Amine
HN
-
82.0
13
N
H
CHO
O
14
15
HN
O
-
92.0
N
H
CHO
CHO
CHO
NH
NH
NH
80.0
15.4
-
-
NH
NH
16
17
-
NH
66.2
CHO
NH2
N
18
4.8
4.4
H
91.0
54.0
CHO
NH2
N
H
19
20
O
H
N
NH2
NH2
2.0
30.8
trace
10.5
O
21
N
H
-
-
NH2
NH2
H
N
O
22
23
H
N
O
18.2
27.5
-
-
H
24
NH2
N
O
Reaction conditions: benzaldehyde (1 mmol); aniline (1 mmol); catalyst weight (50 mg); solvent 3 ml; reaction temperature: 60 °C, reaction
time: 30 min H2 atmosphere
a
Yields were determined by GC–MS analysis
123

394
A. Srivani et al.
100
90
80
70
60
50
40
30
20
10
0
shown in Table 2. It is found that DMF was best solvent as
it gave high yield compared to other solvents. The high
activity with DMF solvent might be related to stabilization
of the imine–pd complex formed initially stabilized by
DMF compared to other solvents. Such stabilization of
imine–Pd complex by DMF was reported [27]. The stabi-
lized imine–Pd complex undergoes easy reduction to yield
amine. It is noteworthy to mention that the present catalyst
is active in many solvents including water.
Amine
Imine
Various aldehydes and amines were subjected to
reductive amination over 20% PdMPA/SiO2 catalyst and
the results are presented in Table 3. The reductive amina-
tion of aldehydes are more facile than ketones. At the same
time aromatic aldehydes are more active than aliphatic
aldehydes. Aromatic aldehydes with electron donating
groups smoothly underwent reductive amination to give
their corresponding N-phenyl amines in good yield without
affecting the functional groups. Aromatic aldehydes with
halo group gave desired amine in good yields and the
reactivity of fluorine and chlorine containing aldehydes are
more active than bromo aldehydes. Aromatic aldehydes
and amines with electron withdrawing group such as –NO2
gave low yield. This might be because of the reduction of
NO2 group during the reaction. In the case of acetophe-
none, the formation of 1-phenylethanol was more than
actual amine product. The formation of 1-phenylethanol by
the reduction of ketone was found to be the major pathway
5
10
15
20
25
30
Time (min)
Fig. 3 Time on stream analysis for the synthesis of amine over 20%
PdMPA/SiO2. Reaction conditions: benzaldehyde (1 mmol); aniline
(1 mmol); catalyst weight (50 mg); solvent 3 ml; reaction tempera-
ture: 60 °C
catalyst also yielded reasonably high amount of amine.
Based on the above results the reaction path way over the
catalyst can be illustrated as shown in Scheme 1. Suitable
solvent system for reductive amination of aniline and
benzaldehyde as a test reaction was checked by carrying
the reaction with different solvents and the results are
Scheme 2 Plausible reaction
mechanism for reductive
amination over silica supported
palladium exchanged
H
O
Pd
catalyst
H2
NH
H
molybdophosphoric acid
catalyst
NH2
H
H2O
N
C
HH
H
Pd
catalyst
O
Pd
H
catalyst
H
NH CH2
H
Pd
O
Pd
H
catalyst
CHO
123

Reductive Amination of Carbonyl Compounds
395
used (after 4th cycle) catalysts were estimated. The Pd
content in these catalysts was 3.067 and 3.052 mmol for
fresh and used catalysts respectively. The consistent
activity upon reuse and the similar content of Pd before and
after reaction reiterates the heterogeneity of the catalyst.
Table 4 Recycling results of 20% PdMPA/SiO2 catalyst
S.
No. of
Imine
Amine
Alcohol
no. recycles yield (%) yield (%) yield (%)
Catalyst
recovery (%)
1
2
3
4
0
1
2
3
0.8
0.6
1.3
1.7
93
90
87
84
1.2
0.9
0.6
0.5
–
95
92
90
4 Conclusions
in this case. Hetero atom containing amines undergo
reductive amination smoothly with high yield. This catalyst
is also effective when secondary amines with or without
branching is used for the reductive amination with alde-
hydes (Table 3, s.Áno. 15–17).
Silica supported palladium exchanged MPA catalyst was
prepared with intact Keggin structure. 20% PdMPA/SiO2
was an efficient catalyst for reductive amination of various
aldehydes and ketones. This catalyst is active even when
various secondary, cyclic and acyclic amines are used and
afforded the corresponding secondary and tertiary amines
in high yields. This method is very advantageous in terms
of its mild reaction conditions, mono alkylation than con-
ventional catalytic/reagents and heterogeneity environ-
mentally benign nature of the catalyst.
The time on stream analysis for the reductive amination
over 20% PdMPA/SiO2 catalyst was studied and the results
are shown in Fig. 3. This study was undertaken to know
about the formation of both intermediate imine and product
amine as shown in Scheme 1. Initially at the start of the
reaction the formation of imine is more and as the reaction
progresses the formation of amine is gradually increased.
These results suggest that the reaction undergoes via the
formation of imine which easily undergoes reduction on Pd
sites to yield amine.
Acknowledgments A. Srivani thanks Council of Scientific and
Industrial Research (CSIR), India for financial support in the form of
a Junior Research Fellowship.
The plausible reaction mechanism over this catalyst is
schematically shown in Scheme 2. In this reaction the first
step is the formation of the imine intermediate by the
reaction of condensation between carbonyl compound and
amine on the catalyst surface utilizing the acidic sites
present on the catalyst surface. This imine was coordinated
with the hydrogen atoms activated by Pd sites of the catalyst
and undergoes subsequent reduction to yield amine deriva-
tive. The time on stream analysis supports the proposed
mechanism as the formation of imine is observed. The cat-
alyst without palladium (20% MPA/SiO2) yielded only the
imine as a main product suggesting the requirement of Pd
for the reduction imine. The formation of imine mainly over
silica supported CuMPA and MPA reiterate the importance
of Pd in reducing the imine that formed on the acidic sites of
the catalyst. The present catalyst overcomes the requirement
of both acid catalyst/reagent along with a reducing agent
generally required for reductive amination.
References
1. Veeraraghavan Ramachandran P, Gagare PD, Sakavuyi K, Clark
P (2010) Tetrahedron Lett 51:3167–3169
2. Grenga PN, Sumbler BL, Beland F, Priefer R (2009) Tetrahedron
Lett 50:6658–6660
3. Rung-Yi L, Chun-I L, Shiuh-Tzung L (2008) Tetrahedron 64:
1213–1217
4. Apodaca R, Xiao W (2001) Org Lett 3:1745–1748
5. Miriyala B, Bhattacharyya S, Williamson JS (2004) Tetrahedron
60:1463–1471
6. Wang C, Pettman A, Bacsa J, Xiao J (2010) Angew Chem Int Ed
49:7548–7552
7. Byun E, Hong B, De Castro KA, Lim M, Rhee H (2007) J Org
Chem 72:9815–9817
8. Pham PD, Bertus P, Legoupy S (2009) Chem Commun 7:
6207–6209
9. Srinivasa Reddy P, Kanjilal S, Sunitha S, Prasad RBN (2007)
Tetrahedron Lett 48:8807–8810
10. Gonzalez-Arellano C, Yoshida K, Luque R, Gai P (2010) Green
Chem 12:1281–1287
11. On-Yi L, Ka-Lun L, Dan Y (2009) Org Lett 11:3302–3305
12. Surya Prakash GK, Do C, Mathew T, Olah GA (2010) Catal Lett
137:111–117
3.1 Recyclability of the Catalysts
13. Enthaler S (2011) Catal Lett 141:55–61
14. Bhattacharyya S (1995) J Org Chem 60:4928–4929
15. Ranu BC, Majee A, Sarkar A (1998) J Org Chem 63:370–373
16. Sato S, Sakamoto T, Miyazawa E, Kikugawa Y (2004) Tetra-
hedron 60:7899–7906
17. Burkhardt ER, Coleridge BM (2008) Tetrahedron Lett 49:
5152–5155
18. Maes BUW, Loones KTJ, Hostyn S, Dielsb G, Rombouts G
(2004) Tetrahedron 60:11559–11564
After completion of the reaction, the catalyst was separated
by simple filtration and washed 2–3 times with DMF and
dried in hot air oven at 120 °C for 1 h. The dried catalyst
was reused. The recovery of the catalyst is varied with in
95–90%. The results obtained by recycling of the catalyst
are shown in Table 4. The amination product after three
cycles was almost constant and the results suggest the
reusability of the catalyst. The Pd content of the fresh and
19. Lee On-Yi, Law Ka-Lun, Ho Chun-Yu, Yang D (2008) J Org
Chem 73:8829–8837
123

396
A. Srivani et al.
´ ´
20. Dominea ME, Hernandez-Sotoa MC, Perez Y (2011) Catal Today
159:2–11
25. Stobbe-Kreemers AW, Van der Lans G, Makkee M, Scholten JJF
(1995) J Catal 154:187–193
21. Kozhevnikov IV (1998) Chem Rev 98:171–198
22. Okuhara T, Mizuno N, Misono M (2001) Appl Catal A: Gen
222:63–77
23. Srivani A, Venkateswara Rao KT, Sai Prasad PS, Lingaiah N
(2010) J Mol Catal A Chem 328:119–123
26. Moghadam M, Tangestaninejad S, Mirkhani V, Mohammadpoor-
Baltork I, Moosavifar M (2009) Appl Catal A: Gen 358:157–163
27. Conti F, Donti M, Pregaglia GF (1971) J Organomet Chem
30:421–429
24. Pasha N, Seshu Babu N, Venkateswara Rao KT, Sai Prasad PS,
Lingaiah N (2009) Tetrahedron Lett 50:239–242
123