One-pot Reductive Amination of Carbonyl Compounds with NaBH4-B(OSO3H)3/SiO2 in Acetonitrile and in Solvent-free Condition

Article abstract of DOI:10.1007/s12039-016-1208-8

An efficient one-pot procedure for the direct reductive amination of aldehyde and ketones was achieved in the presence of sodium borohydride by using B(OSO₃H)₃/SiO₂(SBSA) as the reusable solid catalyst in acetonitrile and solvent-free conditions. Both aromatic and aliphatic aldehyde reacted well to give the corresponding amines in excellent yields. All the products are known and well-characterized. The catalyst is recoverable and could be easily recycled by filtration and reused several times without any significant loss of its activity. SBSA acts as a dual Br?nsted/Lewis acid that is an air-stable and cost-effective solid acid. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-016-1208-8

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1208-8
REGULAR ARTICLE
One-pot Reductive Amination of Carbonyl Compounds with
NaBH4-B(OSO3H)3/SiO2 in Acetonitrile and in Solvent-free Condition
HOSEIN HAMADI∗ and SAMIRA JAVADI
Chemistry Department, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
Email: H.Hammadi@scu.ac.ir
MS received 6 August 2016; revised 9 November 2016; accepted 9 November 2016
Abstract. An efficient one-pot procedure for the direct reductive amination of aldehyde and ketones was
achieved in the presence of sodium borohydride by using B(OSO3H)3/SiO2(SBSA) as the reusable solid cat-
alyst in acetonitrile and solvent-free conditions. Both aromatic and aliphatic aldehyde reacted well to give the
corresponding amines in excellent yields. All the products are known and well-characterized. The catalyst is
recoverable and could be easily recycled by filtration and reused several times without any significant loss of
its activity. SBSA acts as a dual Brønsted/Lewis acid that is an air-stable and cost-effective solid acid.
Keywords. Reductive amination; boron trisulfunic acid; catalysis; NaBH4.
1. Introduction
a carbon–carbon double or triple bond and other reducible
functional groups such as cyano and nitro groups.
One of the best reagents for reductive amination is
NaBH3CN, which chemoselectively reduces iminium
ions over aldehydes or ketones. However, this reagent
can liberate hydrogen cyanide when the reaction is
quenched, which is highly toxic.6 Another chemoselec-
tive reducing agent that has been used is sodium triace-
toxyborohydride (NaBH(OAc)3), but it is unstable in
hydroxylic solvents such as methanol and water.9
Sodium borohydride (NaBH4) is a safe, green,
environment-friendly and inexpensive reducing agent,
so it has been the conclusive choice for the direct reduc-
tive amination process and has been used with vari-
ous catalysts.12 However, its application is restricted, in
view of the fact that it is accomplished to reduce other
reducible functional groups in the molecule.
NaBH4 is able to reduce imines as well as carbonyls
(aldehydes and ketones) in the same way. To prevent
the reduction of carbonyl group in the one-pot pro-
cess, the carbonyl-amine condensation reaction must
be completed before addition of Sodium borohydride.
NaBH4 has been used in combination with various
catalysts, which assist imine formation, for successful
reductive amination, such as: Cellulose sulfuric acid,13
CeCl3.7H2O,14 SiO2-Zn(BH4)2,15 Ti(OR)4,16 wet-clay-
microwave,17 H2SO4,18 ZrCl4,19 NiCl2,20 H3BO3,21 sil-
ica chloride,22 micellar media,23 H3PW12O40,24 Silica
phosphoric acid,25 Silica-Gel-supported sulfuric acid,26
Amberlyst 15,27 DOWEX(R)50WX8,28 B(C6F5)3,29
microwave mediated,30 and Ni-complex supported
Fe3O4.31
One of the important method for the synthesis of pri-
mary, secondary and tertiary amines is the reductive
amination of aldehydes and ketones.1 Reductive ami-
nation is a great and trustworthy approach for the for-
mation of C–N bonds, which can avoid the problem
of over-alkylation that often accompanies direct alky-
lation of amines with alkyl halides.2 4 In this reaction,
an amine and a carbonyl compound condense to afford
an imine or iminium ion in one- or two-step procedure
that is reduced in situ or subsequently to form an amine
product. Another problem during reductive amination
of carbonyl compounds with primary amines is over-
alkylation and direct reduction of carbonyl compound
to the corresponding alcohol. In these cases, formation
and isolation of the imines which followed by reduction
can avoid the problem, but the need to isolate imines
make its synthetic utility poor.5
A large number of reducing hydride reagents have
been studied for direct reductive amination avoiding the
direct reduction of starting carbonyl compound to the
corresponding alcohol, including sodium cyanoborohy-
dride (NaBH3CN),6 Pyridine–BH3,7 sodium triacetoxy-
borohydride (NaBH(OAc)3),8 hydrosiloxane reagent,9
titanium(IV) isopropoxide,10 and Zirconium (IV) iso-
propoxide.11 However, many of these methods suffer
from diverse disadvantages such as toxic compounds
as by-product, hygroscopicity and thermal instability of
the reagents, incompatibility with compounds containing
∗For correspondence

Hosein Hamadi and Samira Javadi
HO OH
B
HO3SO OSO3H
CHCl3
r.t
SiO2
ClSO3H
HCl
B
SiO2
BSA
OH
N2
OSO3H
SBSA
BSA
Scheme 1. Preparation of B(OSO3H)3/SiO2.
R1
R2
R4
R3
R4
SiO2
R1
R2
B(OSO3H)3
O
H N
N
R3
r.t
NaBH4
CH3CN or Solvent-Free
Scheme 2. Reductive amination of carbonyl compounds by NaBH4 cat-
alyzed by SBSA in CH3CN and under solvent-free conditions.
B(OSO3H)3/SiO2(SBSA)32,33 is a trifunctional inorga-
nocatalyst that works as a strong acid (soluble in water
and polar solvent) which was simply prepared by addi-
tion of chlorosulfonic acid to boric acid under N2
atmosphere at room temperature and then mixed with
SiO2 by 1:5 ratio (Scheme 1) and characterized by
FT-IR spectroscopy. According to the FT-IR spectra,
the bands at ∼ 1160 cm−1 are related to symmetric
stretching vibration of O=S=O, and the band centered
at 650 cm−1 is related to stretching vibration of S–O.
The band at 1105 cm−1 is attributed to O–Si vibra-
tion. The broad and intense O–H stretching absorption
band appears in the region of 3350 cm−1. Due to the
current challenges for developing green and environ-
mentally benign chemical processes, and using solid
reusable catalyst, we report herein the details of direct
reductive amination of aldehydes and ketones using
sodium borohydride-B(OSO3H)3/SiO2 for the first time
(Scheme 2).
condition was added NaBH4 (2 mmol, 72 mg), and then the
reaction mixture was stirred at room temperature (25◦C) with
a magnetic stirrer for 10–20 min. After completion, EtOAc
(10 mL) was added to the reaction mixture, and the cat-
alyst was easily filtered; then, crude product was washed
with H2O (2–10 mL) and a saturated solution of NaHCO3
and dried over anhydrous Na2SO4. After removal of the sol-
vent, the pure product was obtained and further purified by
recrystallization with a suitable solvent (ether or CHCl3).
2.3 Spectral data
1
The structure of the products was confirmed by FT-IR, H,
13C NMR, and compared with the corresponding reported
spectral data.21 29 Spectroscopic data for a selected com-
pound is presented below:
2.3a N-(4-Nitro Benzyl) Aniline (Table 3, Entry 6): 1H
NMR (500 MHz, CDCl3): δ 4.51 (s, CH2), 6.63 (d, 2H,
J=9.5 Hz), 6.80 (t, 1H, J=9 Hz), 7.22 (t, 2H, J=12 Hz), 7.56
(d, 2H, J=11 Hz), 8.22 (d, 2H, 12 Hz); 13C NMR (140 MHz,
CDCl3) δ 47.8 (CH2), 113.2 (CH Ar), 118.5 (CH Ar), 123.9
(CH Ar), 127.8 (CH Ar), 129.4 (CH Ar), 146.9 (CH Ar),
147.2 (CH Ar).
2. Experimental
2.1 General remarks
Chemicals were purchased from Merck and Fluka and used
as received. FT-IR spectra were obtained using BOMEM
MB-Series 1998 FT-IR spectrometer. 1H NMR spectra were
run on Bruker Avance spectrometer (DRX 500 MHz). The
progress of the reaction was followed with TLC, using sil-
ica gel SILG/UV 254 plates. All the products are known and
3. Results and Discussion
We started with optimization of the reaction conditions
by the model reaction of benzaldehyde/aniline at room
temperature. The effects of the reaction conditions,
such as amount of catalyst, reaction time and different
solvents on the catalytic performance of SBSA were
examined. Table 1 summarizes the results obtained for
different amount of catalyst which shows that the best
performance is seen in the presence of 0.05 g amount
of SBSA. The results presented in Table 2 point out
1
were characterized by comparison of their spectra (IR, H
NMR) and TLC with those reported in the literature.
2.2 General procedure
To a mixture of aldehyde (1 mmol), amine (1.2 mmol) and
SBSA (0.05 g) in CH3CN (5 mL) or under solvent-free that the reaction of benzaldehyde and aniline exhibited

One-pot Reductive Amination of Carbonyl
Table 1. Optimization of the amount of catalyst.
As indicated in Table 3, excellent yields were
obtained with electron-withdrawing as well as electron-
donating groups (entries 1–8), Functional groups such
as –Cl, –Br, –NO2, and C=C (Entry 19) present on the
aldehyde remained unaffected. On the other hand, using
different amine component with benzaldehyde shows
that aniline containing an electron-withdrawing group
decreases the reaction yield (entry 11), whereas an ani-
line containing an electron-donating group increased
the product yield slightly (entry 10).
Entry
Catalyst (g)
Time (min)
Yield (%)
1
2
3
4
0.15
0.1
0.05
0.02
10
10
5
50
68
85
80
15
Table 2. Solvent selection.
Entry
Solvent
Time (min)
Yield (%)
Aliphatic and cyclic ketones also undergo reductive
amination effectively to give the corresponding amines
in excellent yields (entries 17–19). In order to illustrate
the scope and limitation of this method, we also exam-
ined aliphatic amines such as benzylamine, pyrrolidine
and morpholine, which have shown excellent yields
(entries 13, 15–17). All the products are known com-
1
2
3
4
5
6
7
H2O
EtOH
CH3CN
PEG-300
THF
CHCl3
Solvent-free
180
90
10
80
70
95
80
60
20
96
50
120
180
5
1
pounds and were checked by the H-chemical shift of
Reaction conditions: 1 mmol benzaldehyde, 1.2 mmol ani-
line and 2 mmol NaBH4 at room temperature.
the CH2 group which comes out around 4.22–4.68 ppm
as a singlet. Also, the NH stretching frequency in the
FT IR spectrum appeared around 3380–3427 cm−1.
This condition has shown that the imine intermedi-
ate was converted easily to the corresponding amine
without any carbonyl reduction to the corresponding
alcohol. On the other hand, the absence of formation
of any over-alkylated amine in this reduction shows the
validity of the catalyst. Since the catalyst was separated
by simple decantation, it was washed with ether and
reused in a subsequent reaction. Yields of the product
the best performance in acetonitrile as the solvent and
under solvent-free conditions.
To explore the scope and limitations of the present
catalyst system, under optimal condition, reductive
amination of various carbonyl compounds and amines
was carried out by using SBSA as the catalyst and
NaBH4 in acetonitrile and under solvent-free condi-
tions, as summarized in Table 3.
Table 3. Reductive aminations of various aldehydes and ketones by using NaBH4 and SBSA under the optimized
conditions a.
Solvent-free
CH3CN
Time (min)
Entry
Aldehyde/Ketone
PhCHO
amine
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
Time (min)
Yield (%)
Yield (%)
1
2
3
4
5
6
7
8
5
20
20
20
20
7
10
10
20
5
10
10
10
10
5
96
90
87
93
96
87
82
90
91
93
80
80
82
85
96
90
91
85
81
5
20
30
20
20
10
15
15
20
10
15
10
20
20
10
10
10
10
20
95
84
74
87
94
80
78
86
90
85
85
70
80
80
91
85
87
84
78
4-MeOC6H4CHO
4-MeC6H4CHO
4-ClC6H4CHO
4-BrC6H4CHO
4-NO2C6H4CHO
3-NO2C6H4CHO
4-HOC6H4CHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
Cyclohexanone
Cyclohexanone
Cinnamylaldehyde
PhNH2
9
4-BrC6H4NH2
4-MeOC6H4NH2
4-NO2C6H4NH2
3,4-Di MeC6H4NH2
PhCH2NH2
2-NH2Pyridine
Morpholine
Pyrrolidine
Pyrrolidine
PhNH2
10
11
12
13
14
15
16
17
18
19
5
5
5
5
PhNH2
a Reaction conditions: phenylaldehyde (1 mmol), amine (1.2 mmol), SBSA (0.05 g), and NaBH4 (2 mmol) in CH3CN (5 mL)
or under solvent-free, at room temperature.

Hosein Hamadi and Samira Javadi
Table 4. Comparison of the results obtained from the SBSA-catalyzed reductive amination of aniline with benzaldehyde
with other catalysts.
Entry
Catalyst
Solvent
Time (min)
Yield (%)
Ref.
14
29
22
13
13
25
1
2
3
4
5
6
7
8
CeCl3.7H2O
Ni-ACF@Am-SiO2@Fe3O4
Silica Chloride
Cellulose sulfonic acid
Cellulose sulfonic acid
Silica phosphoic acid
B(OSO3H)3/SiO2
EtOH
-
-
EtOH
-
THF
CH3CN
-
8h
20
2
45
4
15
10
5
93
99
96
94
96
95
95
96
This work
This work
B(OSO3H)3/SiO2
O
R
SiO2
B
R
R
H
OSO3H
N
R
R
H
O
R
SiO2
B
R
R
OSO3
R
R
NH
R
H
N
H
R
HO
R
R
R
B
N
R
H B H
H
N
R
H2O
R
R
SiO2
B
OSO3
R
R
R
SiO2
B
H2O
SiO2
OSO3
OSO3
Scheme 3. Proposed reaction mechanism for the reductive amination catalyzed by SBSA
decreased only slightly after reuse of catalyst five the electrophilic character of the starting carbonyl
times. For example, the reductive amination of ben- compound. Subsequent nucleophilic addition of the
zaldehyde and aniline afforded the corresponding N- amine provides the adduct intermediate which leads
benzyl aniline in 96, 94, 90, 89 and 88% yields over to iminium compound after dehydration, which is fol-
five cycles.
lowed in a subsequent reaction by reduction afforded
SBSA acts as a dual Brønsted/Lewis acid and the the product.
catalytic activity depends on both sulfuric (OSO3H)
and boron sites.32 In the present work, we showed the
catalytic performance of SBSA for direct reductive ami- 4. Conclusions
nation. To show the value of the present work, we com-
pared the results of SBSA in the reductive amination In this investigation, we have shown that NaBH
/
4
of aniline with benzaldehyde to other catalysts at 25◦C
B(OSO3H)3/SiO2 is an efficient reagent for the synthe-
sis of amines by direct reductive amination of carbonyl
compounds with various amines. This method afforded
amines as the only isolated products at room temper-
ature. The neutral reaction conditions, simple workup,
isolation of pure products, high yields and use of safe
and inexpensive reagents are notable advantages of the
present method. These advantages make the procedure
as an attractive new protocol for reductive amination
(Table 4). As shown in Table 4, SBSA is a more efficient
catalyst and gives high yields in a shorter reaction time.
In addition, the advantages of SBSA are its recyclability,
easy work-up and avoidance of over-alkylation and
alcohol formation in this condition.
A possible mechanism for the direct reductive amina-
tion catalyzed by SBSA has been proposed (Scheme 3).
SBSA as Bronsted acid plays a role in increasing

One-pot Reductive Amination of Carbonyl
borohydride with CeCl3.7H2O as catalyst J. Chem. Res.
of aldehydes and it could be a useful addition to the
present methodologies.
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Supplementary Information (SI)
All additional information pertaining to characterization of
the products and catalyst using NMR technique (Figures S3–
S5) and IR spectra (Figures S1, S6–S23) are given in the sup-
porting information. Supplementary Information is available
at http://www.ias.ac.in/chemsci.
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