Reductive amination of aldehydes and ketones under heterogeneous and solvent-free conditions using sodium-borohydride and silica-gel-supported sulfuric acid

Article abstract of DOI:10.1080/00397910802691882

A regioselective and convenient procedure for preparation of amines by reductive amination of aldehydes and ketones using sodium borohydride in the presence of sulfuric acid supported on silica gel as an active, inexpensive, and recoverable catalyst under heterogeneous and solvent-free conditions at room temperature is described.

Full text of DOI:10.1080/00397910802691882

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Reductive Amination of
Aldehydes and Ketones Under
Heterogeneous and Solvent-
Free Conditions Using Sodium-
Borohydride and Silica-
Gel–Supported Sulfuric Acid
a
a
Heshmatollah Alinezhad , Mahmood Tajbakhsh
&
a
Mahboobeh Zare
a
Faculty of Chemistry, Mazandaran University,
Babolsar, Iran
Version of record first published: 14 Jul 2009.
To cite this article: Heshmatollah Alinezhad, Mahmood Tajbakhsh & Mahboobeh Zare
2009): Reductive Amination of Aldehydes and Ketones Under Heterogeneous and
(
Solvent-Free Conditions Using Sodium-Borohydride and Silica-Gel–Supported Sulfuric
Acid, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:16, 2907-2916
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1
Synthetic Communications , 39: 2907–2916, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802691882
Reductive Amination of Aldehydes and Ketones
Under Heterogeneous and Solvent-Free
Conditions Using Sodium-Borohydride
and Silica-Gel–Supported Sulfuric Acid
Heshmatollah Alinezhad, Mahmood Tajbakhsh,
and Mahboobeh Zare
Faculty of Chemistry, Mazandaran University, Babolsar, Iran
Abstract: A regioselective and convenient procedure for preparation of amines by
reductive amination of aldehydes and ketones using sodium borohydride in the
presence of sulfuric acid supported on silica gel as an active, inexpensive, and
recoverable catalyst under heterogeneous and solvent-free conditions at room
temperature is described.
Keywords: Heterogeneous system, one-pot reaction, reductive amination, solvent
free
The reductive amination reaction remains one of the most powerful and
widely utilized transformations available to practitioners of chemical
[1]
synthesis in the modern era. Synthesis of secondary and tertiary amines
by this reaction is usually a relatively fast and efficient reaction, provid-
ing synthetically useful organic intermediates and pharmaceutically
[2]
relevant compounds. The sequence proceeds through the formation
of an imine or iminium intermediate upon reaction of a carbonyl com-
pound with a primary or secondary amine followed by in situ reduction
[3]
[4]
to an amine of higher order. Catalytic hydrogenation is a common
method for this conversion but has limited use with compounds contain-
ing reducible functional groups such as nitro, cyano, and CꢀC multiple
Received October 12, 2008.
Address correspondence to Heshmatollah Alinezhad, Faculty of Chemistry,
Mazandaran University, Babolsar, Iran. E-mail: heshmat@umz.ac.ir
2
907

2908
H. Alinezhad, M. Tajbakhsh, and M. Zare
bonds. Among the borohydride reagents, sodium cyanoborohydride is
widely used. However, use of excess reagent (up to five-fold) along with
[
5]
toxic cyanide as the by-product limits its wide applications. To further
improve the scope and selectivity in reductive amination reactions,
[
6]
several other reducing systems including Bu SnH, Bu SnClH and Bu
2
3
[8]
2
[
7]
[9]
SnIH, phenylsilane–dibutyltin dichloride, and decaborane have
been described. All these methods require stoichiometric or excess quan-
tities of the hydrides, which are generally highly reactive and expensive.
[
10]
Other hydrides such as TiCl(OiPr) -NaBH(OAc) , thiourea–Hantzsch
3
3
[
11]
[12]
[13]
ester, Et SiH–trifluoroacetic acid, NaBH ꢁ H BO , dibutylchloro-
3
4
3
[15]
3
[14]
tin hydride complex,
Zr(BH ) Cl (dabco) ,
4
N-methyl piperidine
2
2
2
[16]
[17]
zinc borohydride, and NaBH in micellar media have also been used
4
for this purpose. Of the commercially available metal hydrides, NaBH4
has been used extensively for reduction of organic substrates because of
environmental and economic considerations.
During the past decade, solid acid catalysts played a significant role
in the development of cleaner technologies through their abilities to act as
catalysts and support reagents, entrain by-products, avoid aqueous
[
18]
workup, and influence product selectivity.
Recently, silica-gel–supported sulfuric acid (SSA) has been found to be
an efficient catalyst for a variety of acid-catalyzed reactions, such as dehy-
dration of alcohols, preparation of a,b-unsaturated keto enol-ethers, pre-
[19]
paration and hydrolysis of 1,3-dioxolanes, and protection of alcohols.
Heterogeneous reactions have received attention in recent years
[
20]
because of their greater selectivity and simple reaction workup.
In addition, solvent-free conditions are especially suitable for providing
[21]
an ecofriendly system. Volatile, toxic, and hazardous organic solvents
[
are continuously being replaced by the use of solvent-free techniques.
22]
Now, we report efficient procedures from environmental and eco-
nomic points of view for the reductive amination of carbonyl compounds
with excellent yields.
In these methods, aldehydes or ketones are mixed with an amine,
NaBH , and SSA in a single operation without preformation of an inter-
4
mediate imine or iminium salt (Scheme 1) under a heterogeneous system
and in solvent-free conditions (methods 1 and 2).
To find the optimum reaction conditions, we carried out a series of
experiments, and results are tabulated in Table 1. As shown in Table 1,
reductive anilation of benzaldehyde with NaBH4 in the presence of
SSA afforded the highest yield under the heterogeneous system (entry 5)
and solvent-free conditions (entry 4) in a short time. Using H SO or
2
4
silica gel instead of SSA in this reaction gave a low yield of the product
with a longer reaction time (entries 1 and 2), which implies the role of
SSA catalyst in this reaction.

Reductive Amination of Aldehydes and Ketones
2909
Scheme 1.
To show the generality of optimal conditions, we have examined
reductive amination of various aldehydes and ketones with aliphatic
and aromatic amines, and results are shown in Table 2. Under the
described conditions, the reactions were completed in 1–20 min and gave
the corresponding amines in excellent yields.
As shown in Table 2, reducible functional groups including cyano
and nitro groups yielded anticipated products without detectable reduc-
tive side products (Table 2, entries 2 and 3).
In the case of a,b-unsaturated aldehydes such as cinnamaldehyde, the
reductive amination was successfully achieved in excellent yield without
reduction of the C¼C bond (Table 2, entry 8). It is interesting to
mention that weakly acidic anilines such as nitro and choloroanilines
do not usually undergo clean reductive amination reactions. NaBH CN,
3
the most widely used reagent for the reductive amination of aldehydes
[
23]
and ketones, is sluggish and inefficient reagent for this purpose.
We have found that both 4-nitro and 4-chloro anilines under optimal
conditions react efficiently with benzaldehyde within 2–20 min (Table 2,
a
Table 1. Reductive amination of benzaldehyde with aniline
Entry
Catalyst
SO
Silica gel
SSA
SSA
Amount of catalyst (g)
Time (h)
Yield (%)
b
1
2
3
4
5
H
2
4
0.05 (0.02)
2 (2)
2 (2)
2 (2)
1.2 (0.03)
0.07
60 (80)
51 (79)
50 (80)
95 (98)
95
0.5 (0.2)
0.1
0.2
c
SSA
0.5
a
Benzaldehyde (1 mmol) mixed with aniline (1 mmol) and treated with NaBH4
1 mmol) and catalyst in THF (5 ml) at room temperature.
(
(
b
Benzaldehyde (1 mmol) mixed with aniline (1 mmol) and treated with NaBH
1 mmol) and catalyst under solvent-free conditions at room temperature.
4
Amount of catalyst, reaction time, and yields of the reactions are given in
parentheses.
c
0
.5 g SSA contains 0.05 g H SO (98%).
2 4

2
910

2
911

2
912

Reductive Amination of Aldehydes and Ketones
2913
entries 6 and 7). 4-Nitroaniline under heterogeneous reaction conditions
with 0.5 mmol excess of NaBH afforded 98% of N-benzyl-4-nitroaniline
4
(
Table 2, entry 7). Similary aliphatic and cyclic ketones underwent this
reaction to give the corresponding amines in excellent yield (Table 2,
entries 14–20). However, to examine a greater range of amines to better
illustrate the scope and limitation of the method, we have investigated the
reaction with both primary and secondary amines, such as allylamine,
piperidine, pyrrolidine, and morpholine, using PhCHO as representative
aldehyde and cyclohexanone and 2-heptanone as representative ketones
(
Table 2, entries 10–20). Reductive amination of aliphatic aldehyde such
as butanal with aniline, allyl amine, and piperidine also gave excellent
yields of the corresponding amines (Table 2, entries 21–23).
In summary, we have described an effective, fast, regioselective, and
very simple method for the preparation of amines by direct reductive
amination of diffrent aldehydes and ketones with various amines using
sodium borohydride in the presence of SSA as a stable solid acid under
heterogeneous and solvent-free conditions at room temperature. The
advantages of these systems, such as simple workup procedure, regiose-
lective and rapid reduction, excellent yields, energy savings, avoidance
of solvent waste dangers and toxicity, neutral reaction conditions, and
use of safe and inexpensive reagents with no special handling techniques
(which is important from an environmental point of view) make these
methods good alternatives to the existing methods.
EXPERIMENTAL
General
Materials were purchased from Fluka and Merck companies. SSA
[
35]
was prepared according to the reported procedure.
characterized by comparison of their spectroscopic data ( H NMR, IR)
and physical properties with those of authentic samples.
Products were
1
General Procedure for the Reductive Amination of Carbonyl Compounds
in THF (Method 1)
Carbonyl compound (1 mmol) and amine (1 mmol) were mixed in THF
(
5 ml) and treated with sodium borohydride (1 mmol), and the pH was
adjusted to neutral by addition of SSA (0.5 g). The mixture was stirred
at room temperature for the appropriate time (Table 2). After completion
of the reaction, as indicated by thin-layer chromatography (TLC),

2914
H. Alinezhad, M. Tajbakhsh, and M. Zare
solvent was evaporated and the crude product was purified by column
chromatography on silica gel (eluent; hexane=EtOAc: 10=1).
General Procedure for the Reductive Amination of Carbonyl Compounds
Under Solvent-Free Conditions (Method 2)
Carbonyl compound (1 mmol) and amine (1 mmol) were ground with
NaBH (1 mmol) in the presence of SSA (0.2 g) under solvent-free condi-
tions at room temperature. The reactions were immediately completed
4
(monitored by TLC). The crude product was purified by column chroma-
tography on silica gel (eluent; hexane=EtOAc: 10=1).
ACKNOWLEDGMENT
This work was supported by a research grant from Mazandaran
University, Iran.
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