Reductive amination of aldehydes and ketones using sodium borohydride in the presence of silica chloride under solvent-free conditions

Article abstract of DOI:10.1016/j.cclet.2009.07.018

A simple and convenient procedure for the preparation of amines from aldehydes and ketones with sodium borohydride activated by silica chloride as a catalyst under solvent-free conditions is described. A variety of aliphatic and aromatic aldehydes, ketones and amines when mixed with NaBH₄/silica chloride at room temperature, afforded excellent yield of the corresponding amines.

Full text of DOI:10.1016/j.cclet.2009.07.018

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 47–50
www.elsevier.com/locate/cclet
Reductive amination of aldehydes and ketones using sodium
borohydride in the presence of silica chloride under
solvent-free conditions
*
Heshmatollah Alinezhad , Mahmood Tajbakhsh, Neda Hamidi
Faculty of Chemistry, Mazandaran University, Babolsar, Iran
Received 18 May 2009
Abstract
A simple and convenient procedure for the preparation of amines from aldehydes and ketones with sodium borohydride activated
by silica chloride as a catalyst under solvent-free conditions is described. Avariety of aliphatic and aromatic aldehydes, ketones and
amines when mixed with NaBH4/silica chloride at room temperature, afforded excellent yield of the corresponding amines.
# 2009 Heshmatollah Alinezhad. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Reductive amination; Silica chloride; Solvent-free conditions; Sodium borohydride
Amines are very important industrial organic compounds that have found widespread applications [1]. Two of the
most common methods to prepare amines are the reductive amination of carbonyl compounds and the hydrogenation
of nitriles. Reductive amination of aldehydes and ketones, in which a mixture of an aldehyde or ketone and an amine is
treated with a reductant in a one-pot fashion, is one of the most useful methods for the preparation of secondary or
tertiary amines in biological and chemical systems [2].
Sodium cyanoborohydride [NaBH3CN] [3] and sodium triacetoxy borohydride [NaBH(OAc)3] [4] are two
important reagents to achieve this transformation. Other hydrides such as NaBH4–H3BO3 [5], NaBH4–guanidine
hydrochloride [6], Ti(O-iPr)4/NaBH4 [7], Cu(PPh3)2BH4 [8], Zr(BH4)2Cl2(dabco)2 [9], NaBH4 in micellar media [10],
N-methyl piperidine zinc borohydride [11], NaBH4–H3PW12O40 [12], NaBH4–silica phosphoric acid [13], and N-
methyl pyrrolidine zinc borohydride [14] used for this purpose. However, some of these reagents may have one
drawback or another. For example, the use of an expensive and highly toxic NaBH3CN that carries the risk of having
residual cyanide in the product as well as in the work up stream and generates a complex mixture of starting material
and partially products [15].
Solvent-free condition is especially suitable for providing an eco-friendly system. Currently, much emphasize has
been given to the use of inorganic reagents in organic reactions, because of environmental and economic
considerations, simple experimental procedures, mild reaction conditions, minimization of chemical waste and easier
work up compare with the similar reactions using organic ones [16,17]. Silica chloride is a mild oxophilic reagent, and
its handling is much easier than SOCl2 and TMSCl, which have toxic and corrosive vapors [18].
* Corresponding author.
E-mail address: heshmat@umz.ac.ir (H. Alinezhad).
1001-8417/$ – see front matter # 2009 Heshmatollah Alinezhad. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.07.018

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H. Alinezhad et al. / Chinese Chemical Letters 21 (2010) 47–50
Scheme 1. Reductive amination of aldehydes and ketones using sodium borohydride in the presence of silica chloride under solvent-free conditions.
Now we report an efficient and smooth reductive amination of a variety of carbonyl compounds using NaBH4 in the
presence of silica chloride under solvent-free conditions (Scheme 1).
1. Experimental
Materials were purchased from Fluka and Merck Companies. The reaction were monitored by TLC using silica gel
plates and the products were purified by flash column chromatography on silica gel (Merck; 230–400 mesh) and were
identified by comparison of their spectra and physical data with those of the authentic samples. 1H NMR spectra were
measured at 500 MHz on a JEOL spectrometer with tetramethylsilane (Me4Si) as an internal reference and CDCl3 as
the solvent. IR spectra were recorded on Pye-unicam SP 1100 spectrophotometer.
Thionyl chloride (40 mL) was added to an oven-dried (120 8C, vacuum) silica gel (10 g) in a round-bottomed flask
(250 mL) equipped with a condensor and a drying tube and refluxed for 48 h. The unreacted thionyl chloride was
distilled off. The resulting white-grayish powder was flame-dried and stored in a tightly capped bottle. The content of
chloride in silica chloride measured (0.7%) using argentometric method. This silica chloride can be used for months
without loosing its activity [19].
NaBH4 (1 mmol) and silica chloride (0.2 g) was ground with amine (1 mmol) and carbonyl compound (1 mmol) in
a pestle at room temperature. After completion of the reaction, as indicated by TLC, the mixture was washed three
times with CH2Cl2 or ether (3Â 25 mL) and the combined organic solvent was dried over anhydrous Na2SO4.
Evaporation of the solvent gave the crude amine. If necessary the crude products were further purified in a short
column of silica gel.
2. Results and discussion
We initially examined reductive amination of benzaldehyde with aniline using NaBH4 in the presence of silica
chloride. After work up of the reaction mixture, N-benzylaniline was obtained in excellent yield (96%, Table 1, entry
1). We then applied this optimal condition for the reductive amination of various aldehydes and ketones with aliphatic
and aromatic amines and results are shown in Table 1. All reactions were completed in less than 3 min and TLC
showed complete disappearance of imines.
As show in Table 1, aniline and its analogues were reacted with aromatic aldehydes to give the corresponding
amines in excellent yields (entries 1–5 and 9). Weakly basic anilines such as p-nitro and p-chloro anilines gave
satisfactory results, although the commonly used reagents such as [NaBH3CN] [3] and [NaBH(OAc)3] [4] give only
low yields of the corresponding amines in long reaction times (entries 6 and 7).
In the case of a,b-unsaturated aldehydes such as cinnamaldehyde, the reductive amination was successfully
achieved in excellent yield, without reduction of the C C bond (entry 8). We have also found that morpholine,
piperidine and pyrrolidine react efficiently with benzaldehyde to produce their corresponding amines in excellent
yields (entries 10–12).
Under reaction conditions allylamine was reacted immediately with benzaldehyde and cyclohexanone to afford the
expected amines without reduction of C C bond (entries 13 and 18). Similarly aliphatic ketones (entries 19 and 20)
and acyclic ketones (entries 14–18) when reacted with aromatic or aliphatic amines, immediately afforded the
corresponding amines in excellent yields. Finally aliphatic aldehydes such as butyraldehyde under the same reaction
conditions with aniline gave immediately an excellent yield of N-butyraniline (entry 21). This is interesting to mention
that this system did not reduce the carbonyl groups and this selectivity allows for a convenient direct reductive
amination procedure. Another feature of this procedure is the chemoselective reductive preparation of amines having
nitro and cyano groups since these groups are not reduced under optimal reaction conditions (entries 2, 3 and 7).
We have proposed a mechanism in which the role of silica chloride in the reactions is clarified (Scheme 2).

H. Alinezhad et al. / Chinese Chemical Letters 21 (2010) 47–50
49
Table 1
Reductive amination of aldehydes and ketones using sodium borohydride–silica chloride under solvent-free condition.a,b
Entry
Compound
Amine
Time (min)
Yield (%)c
1
2
PhCHO
PhNH2
2
96
91
89
90
95
95
96
98
92
95
95
95
91
95
90
92
94
93
92
97
94
90
4-CN-PhCHO
4-NO2-PhCHO
4-OMe-PhCHO
2-Cl-PhCHO
PhCHO
PhNH2
2
3
PhNH2
2
4
PhNH2
2
5
PhNH2
3
6
4-Cl-PhNH2
4-NO2-PhNH2
PhNH2
Immediately
3
7
PhCHO
8
PhCH CHCHO
PhCHO
2
9
PhNHMe
Morpholine
Piperidine
Pyrrolidine
CH2 CHCH2NH2
PhNH2
Immediately
3
10
11
12
13
14
15
16
17
18
19
20
21
22
PhCHO
PhCHO
Immediately
Immediately
Immediately
Immediately
Immediately
Immediately
Immediately
Immediately
Immediately
Immediately
Immediately
Immediately
PhCHO
PhCHO
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
2-Heptanone
2-Heptanone
Butanal
Pyrrolidine
Piperidine
Morpholine
CH2 CHCH2NH2
PhNH2
Pyrrolidine
PhNH2
2-Heptanone
Morpholine
a
Reactions were carried out at room temperature and molar ratio of reagent/carbonyl compound/amine was 1/1/1.
All products were characterized spectroscopically (1H NMR, IR) and showed physical and spectral data in accordance with their expected
b
structure and by comparison with authentic samples.
c
Yields refer to isolated pure products.
Scheme 2. Suggested mechanism.
Reusability of silica chloride was investigated in this transformation. We found out that the reactivity of catalyst
does not change and we have seen the same yield and reaction time without any further treatment.
3. Conclusion
In this study, we have described an efficient, rapid and chemoselective method for the synthesis of amines by
reductive amination of carbonyl compounds with various amines using sodium borohydride and silica chloride. The
scope of the reaction has been demonstrated with aliphatic, aromatic, cyclic and acyclic carbonyl compounds with
primary and secondary amines. This method, has afforded amines as the only isolated products at room temperature
under neutral, solventless and environmentally benign conditions. NaBH4/silica chloride is an inexpensive, stable, safe
to handle and a bench top reducing agent.
Acknowledgment
Financial support of this work from the Research Council of Mazandaran University gratefully acknowledged.

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H. Alinezhad et al. / Chinese Chemical Letters 21 (2010) 47–50
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