One-pot reductive amination of carbonyl compounds using sodium borohydride-amberlyst 15

Article abstract of DOI:10.1080/00397910903026731

A fast, efficient, and high-yielding method for the preparation of amines by reductive amination of aldehydes and ketones using sodium borohydride in the presence of Amberlyst 15 in tetrahydrofuran and under solvent-free conditions at room temperature is described.

Full text of DOI:10.1080/00397910903026731

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One-Pot Reductive Amination of
Carbonyl Compounds Using Sodium
Borohydride–Amberlyst 15
a
a
Heshmatollah Alinezhad , Mahmood Tajbakhsh & Nastaran
a
Mahdavi
a
Faculty of Chemistry, Mazandaran University, Babolsar, Iran
Version of record first published: 04 Mar 2010
To cite this article: Heshmatollah Alinezhad, Mahmood Tajbakhsh & Nastaran Mahdavi (2010): One-
Pot Reductive Amination of Carbonyl Compounds Using Sodium Borohydride–Amberlyst 15, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:7, 951-956
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1
Synthetic Communications , 40: 951–956, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903026731
ONE-POT REDUCTIVE AMINATION OF CARBONYL
COMPOUNDS USING SODIUM BOROHYDRIDE–
AMBERLYST 15
Heshmatollah Alinezhad, Mahmood Tajbakhsh, and
Nastaran Mahdavi
Faculty of Chemistry, Mazandaran University, Babolsar, Iran
A fast, efficient, and high-yielding method for the preparation of amines by reductive
amination of aldehydes and ketones using sodium borohydride in the presence of Amberlyst
1
5 in tetrahydrofuran and under solvent-free conditions at room temperature is described.
Keywords: Amines; carbonyl compounds; reductive amination; sodium borohydride
INTRODUCTION
Reductive amination of carbonyl compounds is a very important methodology
[
1]
for chemists to target the synthesis of secondary or tertiary amines.
Some reducing agents have been developed for these tandem reactions such as
[
NaBH CN, which is expensive, may contaminate the product with NaCN, and may
2]
3
[3]
generate toxic HCN upon workup. Furthermore, it is necessary to use an excess
amount of the amines (up to five-fold) to limit or prevent the competitive reduction
of the carbonyl groups. Clearly, the use of NaBH CN is not environmentally friendly,
3
and it is not accepted in industry.
Many other reducing agents, such as NaBH(OAc) , pyridine–BH , ZnCl2–
[
4]
[5]
3
3
[
6]
[7]
[8]
[9]
NaBH4, silica gel–Zn(BH ) , ZrCl –NaBH , NaBH –H SO , NaBH –wet clay
4 2
4
4
4
2
[11]
4
4
[10]
[12]
with microwaves, Bu SnH–dimethyl formamide (DMF), Et SiH–CF CO H,
and NaBH –Mg(ClO ) , have been developed. Most are associated with expensive
4
3
3
3
2
[13]
4 2
and flamable reagents, utilization of complex catalysts, and poor product yield even
[
14]
though conversion of the aldehyde is high in some cases. In many instances, a large
excess of amine was used to improve the yield and also to prevent reduction of the
aldehydes to alcohols.
Recently, we reported some reagents for this purpose such as Zr(BH ) Cl
2
4
2
[
15]
[16]
(DABCO) ,
piperidine,
NaBH4 in micellar media,
[18]
zinc borohydride N-methyl
[19]
2
[
17]
NaBH –H PW O ,
12 40
NaBH –silica phosphoric acid,
4
and zinc
4
3
[20]
borohydride N-methyl pyrrolidine.
Received April 18, 2009.
Address correspondence to Heshmatollah Alinezhad, Faculty of Chemistry, Mazandaran
University, Babolsar, Iran. E-mail: heshmat@umz.ac.ir
9
51

952
H. ALINEZHAD, M. TAJBAKHSH, AND N. MAHDAVI
Scheme 1. Reductive amination of aldehydes and ketones using sodium borohydride in the presence of
Amberlyst 15.
We report here a method for the efficient reductive amination of a series of
þ
aldehydes and ketons using NaBH in the presence of Amberlyst 15 (H form)
4
(Scheme 1).
RESULTS AND DISCUSSION
We initially studied the direct reductive amination of benzaldehyde and aniline
þ
in the presence of NaBH and Amberlyst 15 (H form) in tetrahydrofuran (THF)
4
(method 1) and under solvent-free conditions (method 2). In both methods, the
reaction was carried out with an equimolar ratio of benzaldehyde, aniline, and
sodium borohydride, and the pH of the mixture was adjusted to neutrality by
addition of Amberlyst 15 at room temperature.
In method 1, after 1 h, thin-layer chromatography (TLC) showed complete
disappearance of imine, and in method 2, the reaction took place within 20 min.
After workup of the reaction mixture, N-benzylaniline was obtained in excellent
isolated yields (94 and 96%). Under these conditions, carbonyl compounds or amines
carrying both electron-donating and electron-withdrawing substituents produced the
corresponding amines with high regioselectivity. As indicated in Table 1, a variety of
aldehydes and ketones, when treated with primary and secondary amines in the
presence of NaBH –Amberlyst 15, afforded the corresponding amines in good to
4
excellent yields at room temperature. It is noteworthy that unsaturated aldehyde
was chemoselectively reduced to the corresponding amine without reduction of the
carbon–carbon double bond (Table 1, entry 16). Similarly, aliphatic and cyclic
ketones underwent reductive amination successfully to give the corresponding
amines in excellent yields (entries 13, 14, and 15).
This method can be used for anilines with electron-withdrawing groups, which
[
2]
[4]
is not possible with NaBH CN and NaBH(OAc)3, the most common reagents
3
used for this purpose (Table 1, entries 8 and 10).
This reaction is of significance because of its versatility and wide application in
industry. The catalyst Amberlyst 15 works under heterogeneous conditions and can

REDUCTIVE AMINATION OF CARBONYL COMPOUNDS
953
a
Table 1. Reductive amination of aldehydes and ketones using NaBH
4
–Amberlyst 15
b
c
Method 1
Method 2
Carbonyl
compound
d
Yield (%)
d
Yield (%)
Entry
Amine
Time (h)
Time (h)
Ref.
1
2
3
4
5
6
7
8
9
PhCHO
4-Cl-PhCHO
4-NO -PhCHO
PhNH
2
2
2
2
2
2
2
1
93
91
92
93
90
95
92
89
95
90
96
97
91
95
94
97
93
0.3
1.9
95
92
89
96
87
97
93
94
97
95
93
98
94
95
96
91
96
22
10
23
23
29
10
23
24
30
25
22
26
22
26
27
23
28
PhNH
PhNH
PhNH
PhNH
PhNH
PhNH
7
2
1
0.3
0.9
4-CN-PhCHO
2-Cl-PhCHO
4-OMe-PhCHO
4.2
13
6.5
1.8
1.5
1.25
0.7
1.7
1.5
2.1
0.25
0.1
1
0.25
0.3
3
4-CH -PhCHO
PhCHO
PhCHO
4-Cl-PhNH
4-CH -PhNH
4-NO -PhNH
2
0.25
0.2
3
2
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
PhCHO
PhCHO
PhCHO
2
2
0.2
Piperidine
Pyrrolidine
0.15
0.15
0.05
Cyclohexanone
Cyclohexanone
2-Heptanone
Cinnamaldehyde
PhCHO
PhNH
Pyrrolidine
2
e
Imm.
PhNH
PhNH
2
0.25
0.4
2
5.7
2.8
PhNH-Me
0.15
a
All reactions were carried out at room temperature, and the molar ratio of reagent–amine–carbonyl
compound was 1:1:1.
b
Method 1: reaction was carried out in THF with 0.1 g Amberlyst 15.
Method 2: reaction was carried out under solvent-free conditions with 0.05 g Amberlyst 15.
c
d
Yield refers to pure isolated product.
Immediately.
e
[
21]
easily be handled and removed by simple filtration.
The use of inexpensive,
recyclable, nonhazardous, and commercially available acid resin makes this method
simple, convenient, and economically viable.
CONCLUSION
We have established a complementary method for the synthesis of secondary
and tertiary amines through a direct reductive amination of aldehydes and ketones
using sodium borohydride–Amberlyst 15 in THF under solvent-free conditions.
Solvent-free conditions can offer a great opportunity for green chemistry. In parti-
cular, the use of an inexpensive, safe, and very common reducing agent requiring
no special techniques is the notable advantage of this procedure.
EXPERIMENTAL
Materials were purchased from Merck. The reactions were monitored by TLC
using silica-gel plates. The products were purified by flash-column chromatography
on silica gel (Merck, 230–400 mesh) and were identified by comparison of their spec-
1
tra [ H NMR and Fourier transform–infrared (FTIR)] and physical data with those
1
of the authentic samples. H NMR spectra were recorded with Brucker DRX500

954
H. ALINEZHAD, M. TAJBAKHSH, AND N. MAHDAVI
Avance 500-MHz spectrometers, using CDCl as solvent. IR spectra were recorded
3
on a Pye-unicam SP 1100 spectrophotometer.
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 then Amberlyst 15 (0.1 g) was added. The mixture was vigorously stirred at
room temperature, and NaBH (1 mmol) was added. The mixture was stirred again.
4
After completion of the reaction as indicated by TLC, the mixture was filtered, and
the residue was washed with Et O (2 ꢀ 15 mL). The solvent was evaporated, and the
2
crude product was purified by short-column chromatography on silica gel (eluent:
n-hexane=EtOAc 18=2). All products were identified by comparison of their
1
HNMR and FTIR spectra and physical data with those of authentic samples.
General Procedure for the Reductive Amination of Carbonyl
Compounds Under Solvent-Free Conditions (Method 2)
Carbonyl compound (1 mmol) and amine (1 mmol) was mixed, and then
Amberlyst 15 (0.05 g) was added. The mixture ground with NaBH (1 mmol) under
4
solvent-free conditions at room temperature. After completion of the reaction as
monitored by TLC, the mixture was washed with Et O (2 ꢀ 25 mL), and the com-
2
bined solvent was dried over MgSO . Evaporation of the solvent and short-column
4
chromatography of the product on silica gel (eluent: n-hexane=EtOAc 18=2) gave the
pure product. After workup, all products were characterized spectroscopically
1
( H NMR and IR) and showed physical and spectral data in accordance with their
expected structure by comparison with authentic samples.
ACKNOWLEDGMENT
Financial support of this work from the Research Council of Mazandaran
University is gratefully acknowledged.
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