Direct reductive amination of carbonyl compounds using sodium borohydride-silica chloride

Article abstract of DOI:10.3906/kim-0903-46

A simple and convenient procedure for reductive amination of aldehydes and ketones using sodium borohydride in the presence of silica chloride as an active, inexpensive, recoverable, and recyclable catalyst is described. The reactions were carried out with equimolar amounts of amine and carbonyl compound using silica chloride-sodium borohydride in THF at room temperature TUeBITAK.

Full text of DOI:10.3906/kim-0903-46

Turk J Chem
34 (2010) , 307 – 312.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-0903-46
Direct reductive amination of carbonyl compounds using
sodium borohydride-silica chloride
Heshmatollah ALINEZHAD∗, Mahmood TAJBAKHSH, Neda HAMIDI
Faculty of Chemistry, Mazandaran University, Babolsar-IRAN
e-mail: heshmat@umz.ac.ir
Received 18.03.2009
A simple and convenient procedure for reductive amination of aldehydes and ketones using sodium
borohydride in the presence of silica chloride as an active, inexpensive, recoverable, and recyclable catalyst
is described. The reactions were carried out with equimolar amounts of amine and carbonyl compound using
silica chloride-sodium borohydride in THF at room temperature.
Key Words: Reductive amination, silica chloride, sodium borohydride, aldehyde, ketone.
Introduction
Reductive amination of carbonyl compounds is a very important methodology for chemists to target the synthesis
of secondary or tertiary amines;1 thus, there are many approaches to carry out this direct process. NaBH3 CN
is a representative reducing agent,2 and various modified borohydride derivatives have been used that involve
NaBH(OAc)3 ,3 NaBH4 -Mg(ClO4)2 ,4 NaBH4 –wet clay,5 Ti(Oi -Pr)4 -NaBH4 ,6 NaBH4 -ZnCl2 ,7 NaBH4 -
NiCl2 ,8 silica gel–Zn(BH4)2 ,9 [Zr(BH4)2 Cl2 (dabco)2 ],10 NaBH4 in micellar media,11 N -methylpiperidine
13
zinc borohydride,12 NaBH4 -H3 PW12 O40
,
NaBH4 -silica phosphoric acid,14 and N -methylpyrrolidine zinc
borohydride.15 However, most of these reagents may have one drawback or another. For example, catalytic
hydrogenation is incompatible with compounds containing carbon–carbon multiple bonds, nitro groups, and
cyano groups.16 Sodium cyanoborohydride and tin hydride17 reagents are highly toxic and generate toxic
by-products such as HCN, NaCN, or organotin compounds upon workup.
Sodium borohydride is an inexpensive, safe to handle, and environmental friendly reducing agent for the
reductive amination of aldehydes and ketones.18 Procedures for using this mild and selective reagent have been
developed for a wide variety of substrates.
∗Corresponding author
307

Direct reductive amination of carbonyl compounds using sodium..., H. ALINEZHAD, et al.,
In recent years, heterogeneous catalysts have gained importance due to environmental and economic
considerations. Among these, the application of silica chloride as a stable heterogeneous catalyst in organic
synthesis has been widely studied. This catalyst is important from an environmental point of view, because it
produces little waste. It also has excellent activity and selectivity even on an industrial scale and in most cases
can be recovered from reaction mixtures and reused.19
Herein we report an efficient and convenient procedure for the reductive amination of a variety of carbonyl
compounds using NaBH4 in the presence of silica chloride at room temperature (Scheme).
1
R
1
R
Silica Chloride
NaBH4, THF
HNR3R4
+
C
O
3
4
N R R
2
R
2
R
3
1
R = H, alkyl, aryl
R = alkyl, aryl
4
2
R = alkyl, aryl
R = H, alkyl
Scheme. Reductive amination of carbonyl compounds using NaBH4 /silica chloride.
Experimental
Materials were purchased from Merck and Fluka companies. The reactions 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. 1 H-
NMR spectra were measured at 500 MHz on a JEOL spectrometer with tetramethylsilane (Me4 Si) as an internal
reference and CDCl3 as the solvent. IR spectra were recorded on Pye-unicam SP 1100 spectrophotometer.
Reductive amination of carbonyl compounds with sodium borohydride-silica chlo-
ride: a general procedure
Silica chloride was prepared according to the reported procedure.20 Carbonyl compound (1 mmol) and amine
(1 mmol) were mixed in THF (5 mL) and then treated with sodium borohydride (1 mmol) and silica chloride
(0.5 g). The mixture was stirred at room temperature. After completion of the reaction, as indicated by TLC,
the mixture was filtered and the residue was washed with CH2 Cl2 (2 × 10 mL). Solvent was evaporated and
the crude product was purified by column chromatography on silica gel (eluent: n-hexane/EtOAc) to afford
the pure amine.
Some of the selected compounds’ spectroscopic data
N -Benzyl-N -phenylamine. (entry 1) IR (neat, cm−1) 3384, 3003, 1600, 1498, 1321; 1 H-NMR (500 MHz,
CDCl3): δ 7.42-7.20 (m, 5H, phenyl), 7.21 (t, 2H, phenyl), 6.77 (t, 1H, phenyl), 6.67 (d, 2H, phenyl), 4.35 (s,
2H, CH2), 4.06 (br, 1H, NH).
308

Direct reductive amination of carbonyl compounds using sodium..., H. ALINEZHAD, et al.,
N -(p-cyanobenzyl)-N-Phenylamine. (entry 2) IR: 3330, 2940, 2850, 2210, 1610, 1530 cm−1 1 H-
;
NMR (500 MHz, CDCl3): δ 7.60 (d, 2H, phenyl), 7.46 (d, 2H, phenyl), 7.15 (m, 2H, phenyl), 6.72 (t, 1H,
phenyl), 6.56 (t, 2H, phenyl), 4.41 (s, 2H, CH2), 4.20 (br, 1H, NH).
N -(p-methoxybenzyl)-N-Phenylamine. (entry 4) 1 H-NMR (500 MHz, CDCl3): δ 7.24 (d, 2H,
phenyl), 7.16 (t, 2H, phenyl), 6.88 (d, 2H, phenyl), 6.66 (m, 3H, phenyl), 4.25 (s, 2H, CH2), 3.99 (br, 1H, NH),
3.79 (s, 3H, OMe).
N -Phenyl-N-(3-phenyl-2-propenyl)aniline. (entry 12) IR: 3315, 3057, 3025, 2930, 2817, 1597,
1494, 1447, 967, 779, 692 cm−1
;
1 H-NMR (500 MHz, CDCl3): δ 7.17-7.38 (m, 5H), 6.73-6.61 (m, 7H), 3.94
(dd, 2H), 3.92 (br s, 1H).
N -methyl-N-phenyl benzylamine. (entry 8) IR: 3411, 3055, 2926, 1602, 1503 cm−1
(500 MHz, CDCl3): δ 7.19-7.31 (m, 7H), 6.70-6.75 (m, 3H), 4.52 (s, 2H), 3.00 (s, 3H).
;
1 H-NMR
Results and discussion
The reductive amination of a wide variety of aldehydes and ketones with primary and secondary amines in the
presence of NaBH4 –silica chloride under neutral conditions was successful and gave the desired products in good
to excellent yields (89%-97%) as summarized in the Table. Under such a condition, carbonyl compounds were
not reduced in the reaction mixture, whereas the imine intermediates were converted easily to the corresponding
amines. This reagent is suitable for use of chemoselective reduction of imines having nitro and cyano groups,
since this reagent cannot reduce the nitro and cyano groups (entries 2, 3, and 6). 4-Nitroaniline under similar
reaction conditions with 0.5 mmol excess of NaBH4 afforded 97% of N -benzyl-4-nitroaniline within 20 min
(entry 6). We found that 4-choloroanilines under optimal conditions efficiently react with benzaldehyde to
produce the corresponding amine within 12 min (entry 7). In the case of α, β-unsaturated aldehydes and
amines such as cinnamaldehyde and allyl amine, the reductive amination was successfully achieved without
reduction of the C=C bond (entries 12, 13, and 16). Aliphatic aldehydes such as butanal underwent reductive
amination successfully to give corresponding amines (entry 14). Reductive amination of cyclic and acyclic
aliphatic ketones such as cyclohexanone and 2-heptanone with different aromatic and aliphatic amines such
as aniline, allylamine, pipyridine, morpholine, and pyrrolidine also gave excellent yields of the corresponding
amines (entries 15-20).
Conclusion
We described an efficient and chemoselective method for the synthesis of amines by reductive amination of
carbonyl compounds with various amines in the presence of sodium borohydride and silica chloride. The scope
of the reaction was demonstrated with aliphatic, aromatic, cyclic, and acyclic carbonyl compounds with primary
and secondary amines. This method afforded amines as the only isolated products at room temperature. The
neutral non-aqueous reaction conditions, simple workup, isolation of pure products, high yields, very short
reaction time, and the use of safe and inexpensive reagent with no special handling technique are the notable
advantages of the present method.
309

Direct reductive amination of carbonyl compounds using sodium..., H. ALINEZHAD, et al.,
Table. Reductive amination of aldehydes and ketones using sodium borohydride-silica chloride at room temperature.a
c
b
Product
Yield (%)
Entry
1
Compound
CHO
Amine
NH2
Time (min)
5
21
CH2NH
95
22
CHO
96
NH2
CH2NH
2
NC
O2N
MeO
9
NC
O2N
MeO
22
89
CHO
CHO
NH2
NH2
CH2NH
CH2NH
3
4
5
5
95
10
CHO
CH2NH
5
96
NH2
5
6
7
7
Cl
Cl
23
NO2
Cl
CHO
CHO
NH2
97
O2N
Cl
CH2NH
20
24
95
NH2
CH2NH
12
6
Me
Me
25
CHO
CHO
90
8
9
NH
CH2N
21
CH2
95
HN
O
5
O
N
21
CH2
HN
95
10
11
Immediately
Immediately
CHO
HN
26
CH2
CH
N
CHO
CH
95
NH
O
22
CH
NH
NH2
CH2
89
12
13
14
15
Immediately
Immediately
Immediately
Immediately
CH
CH
27
CH2
NH2
CH CH2
NH
NH
CH2 CH
95
CHO
CH2
CH2
21
C H O
NH2
NH2
96
28
NH
O
O
95
21
CH2
NH2
CH CH2
NH
CH2 CH
CH2
94
16
Immediately
310

Direct reductive amination of carbonyl compounds using sodium..., H. ALINEZHAD, et al.,
Table. Contunied.
c
b
Product
Yield (%)
Entry
17
Compound
Amine
NH
Time (min)
26
O
N
90
Immediately
21
92
HN
18
Immediately
O
N
22
O
HN
N
O
O
94
19
20
5
5
Me
O
29
NH2
95
CH
NH
ab All reactions were carried out at r.t. 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 structure and by comparison with authentic samples.
c Yields refer to pure isolated products.
Acknowledgements
Financial support of this work from the Research Council of Mazandaran University gratefully acknowledged.
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