One-pot reductive amination of carbonyl compounds using sodium borohydride-cellulose sulfuric acid

Article abstract of DOI:10.5012/bkcs.2010.31.7.1927

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 cellulose sulfuric acid in EtOH and under solvent-free conditions at room temperature is described.

Full text of DOI:10.5012/bkcs.2010.31.7.1927

One-Pot Reductive Amination of Carbonyl Compounds
Bull. Korean Chem. Soc. 2010, Vol. 31, No. 7 1927
DOI 10.5012/bkcs.2010.31.7.1927
One-Pot Reductive Amination of Carbonyl Compounds
Using Sodium Borohydride-Cellulose Sulfuric Acid
Heshmatollah Alinezhad* and Zakieh Tollabian
Faculty of Chemistry, Mazandaran University, Babolsar, Iran. *E-mail: heshmat@umz.ac.ir
Received March 18, 2010, Accepted May 10, 2010
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 cellulose sulfuric acid in EtOH and under solvent-free conditions
at room temperature is described.
Key Words: Cellulose sulfuric acid, Reductive amination, Carbonyl compounds, Amines, NaBH4
Introduction
Now we report that an efficient and smooth reductive ami-
nation of a variety of carbonyl compounds proceed using NaBH4
in the presence of cellulose sulfuric acid both in EtOH as a sol-
vent (Scheme 1) and under solvent-free conditions (Scheme 2).
Direct reductive amination of aldehydes and ketones is a
convenient method for the preparation of secondary and tertiary
amines owing to its simple procedure1 and recent application of
the reaction to combinatorial chemistry is gaining more atten-
tion.2 A variety of reducing agents, such as hydrogen in the
presence of metal catalysts,3 NaBH3CN,4 NaBH(OAC)3,5 silica
gel-Zn(BH4)2,6 Ti(O-i-Pr)4-NaBH4,7 NaBH4-H2SO4,8 NaBH4-
ZrCl4,9 NaBH4-NiCl2,10 NaBH4-wet-clay-microwave,11 pyri-
dine-BH3,12 NaBH4-H3BO3,13 Zr[(BH4)2(Cl)2(dabco)2],14 Et3-
SiH-CF3CO2H,15 NaBH4 in micellar media,16 zinc borohydride
N-methyl piperidine,17 NaBH4-H3PW12O40,18 NaBH4-Silica
phosphoric acid,19 zinc borohydride N-methyl pyrrolidine20
NaBH4-Silica-Gel-supported sulfuric acid,21 NaBH4-Amber-
lyst 1522 and NaBH4-silica chloride23 have been developed.
However, most of these methods suffer from one or more
drawbacks. For example, hydrogenation is not compatible with
compounds that contain a carbon-carbon double or triple bond
and several other reducible functional groups such as nitro,
cyano and furyl groups.24
Experimental
Preparation of cellulose sulfuric acid.27 To a magnetically
stirred mixture of cellulose (5.00 g, DEAE for column chro-
matography, Merck) in CHCl3 (20 mL), chlorosulfonic acid
(1.00 g, 9 mmol) was added dropwise at 0 oC during 2 h. After
completion of the addition, the mixture was stirred for 2 h until
HCl was removed from reaction vessel. Then, the mixture was
filtered and washed with methanol (30 mL) and dried at room
temperature to obtain cellulose sulfuric acid as white powder
(5.22 g). The number of H+ site of cellulose-SO3H (0.50 meq/g)
determined by acid-base titration. This value corresponds to
about 90% of the sulfur content, indicating that most of the
sulfur species on the sample are in the form of the sulfonic acid
groups.
General procedure for the reductive amination of carbonyl
compounds in EtOH (Method Ι). Carbonyl compound (1 mmol)
and amine (1 mmol) were mixed in EtOH (3 mL) and then was
added cellulose sulfuric acid (0.1 g). The mixture vigorously
Usually pyridine-BH3 from commercial sources was utilized
without further purification, because this reagent is quite un-
stable to heat and attempted distillation of the liquid residue at
reduced pressures sometimes resulted in violent decomposi-
tions. Thus, extreme care must be used if this reagent is handled
in large quantities.25 NaBH(OAC)3 is flammable, water-reactive,
and poorly soluble in most of the commonly used organic
solvents. Cyanoborohydride and tin hydrid reagents are highly
toxic and generate toxic by-products such as HCN, NaCN or
organotin compounds upon workup and may result in the con-
tamination of the product with the toxic compounds.26 Further-
more, they are not environmentally friendly and are not accepted
in the concept of green chemistry.
NHR3
O
NaBH4-Cellulose sulfuric acid
EtOH, rt (88 - 98%)
H2NR3
+
R1
R2
R1
R2
R1 = H, alkyl, aryl R2, R3 = alkyl, aryl
Scheme 1. Reductive amination of carbonyl compounds by NaBH4
in the presence of cellulose sulfuric acid in EtOH
Sodium borohydrid is an inexpensive, safe to handle and
environmental friendly reducing agent which rapidly reduces
aldehydes, ketones and acid chlorides.
NHR3
O
NaBH4-Cellulose sulfuric acid
Solvent free, rt (87 - 98%)
H2NR3
+
R1
R2
R1
R2
Cellulose sulfuric acid is very active, stable to air and mois-
ture, nontoxic and inexpensive. Cellulose sulfuric acid is pre-
pared via reaction between cellulose and chlorosulfunic acid.27
In addition, it can be quantitatively recovered by filtration and
reused.
R1 = H, alkyl, aryl R2, R3 = alkyl, aryl
Scheme 2. Reductive amination of carbonyl compounds by NaBH4
in the presence of cellulose sulfuric acid under solvent-free conditions

1928 Bull. Korean Chem. Soc. 2010, Vol. 31, No. 7
Heshmatollah Alinezhad and Zakieh Tollabian
Table 1. Reductive amination of aldehydes and ketones using NaBH4-cellulose sulfuric acida
Method Ιb
Method ΙΙc
Ref.
Carbonyl
Entry
Amine
Compound
Time (min)
Yieldd (%)
Time (min) Yieldd (%)
1
PhCHO
4-Cl-PhCHO
2-NO2-PhCHO
4-CN-PhCHO
2-Cl-PhCHO
4-OMe-PhCHO
4-CH3-PhCHO
PhCHO
PhNH2
PhNH2
45
20
44
125
57
7
45
95
4
94
91
94
92
89
95
91
89
88
95
88
90
93
94
97
98
91
90
95
96
94
97
89
93
95
4
11
24
34
35
6
96
92
88
97
87
97
93
95
89
98
87
92
92
95
95
97
94
92
95
94
96
90
91
94
97
[25]
[11]
[11]
[26]
[27]
[11]
[28]
[26]
[14]
[29]
[11]
[30]
[25]
[13]
[25]
[31]
[35]
[25]
[31]
[25]
[32]
[28]
[30]
[18]
[33]
2
3
PhNH2
4
PhNH2
5
PhNH2
6
PhNH2
7
PhNH2
22
8
8
4-Cl-PhNH2
4-OEt-PhNH2
4-CH3-PhNH2
4-OMe-PhNH2
4-NO2-PhNH2
Morpholine
PhCH2NH2
Piperidine
Pyrrolidine
PhNH2
9
PhCHO
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
PhCHO
12
22
170
7
3
PhCHO
7
PhCHO
5
PhCHO
2
PhCHO
2
2
PhCHO
6
1
PhCHO
6
1
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
2-Heptanone
Cinamaldehyde
Butanal
28
5
4
Piperidine
Pyrrolidine
PhCH2NH2
PhNH2
1
5
1
2
1
4
2
PhNH2
4
2
PhNH2
18
2
5
PhCHO
PhCHO
EtNH2
1
PhNH-Me
8
2
aAll reactions were carried out at room temperature and molar ratio of reagent/amine/carbonyl compound was 1/1/1 and 0.1 g cellulose sulfuric
acid was used. bMethod Ι: Reaction was carried out in EtOH. cMethod ΙΙ : reaction was carried out under solvent-free condition. dYield refer
to pure isolated product.
stirred at room temperature and NaBH4 (1 mmol) was added
and the mixture was stirred. After completion of the reaction as
indicated by TLC, the mixture was filtered and the residue was
washed with CH2Cl2 (2 × 15 mL). The solvent was evaporated
and the crude product was purified by column chromatography
on silica gel (eluent: n-hexane/EtOAc: 18/2).
NaBH4-cellulose sulfuric acid in EtOH as the solvent (method I)
and under solvent-free conditions (method II). In both methods
the reaction was carried out with an equimolar ratio of benz-
aldehyde, aniline and sodium borohydride and the pH of the
mixture was adjusted to neutrality by addition of cellulose sul-
furic acid at room temperature. In method I after 45 min, TLC
showed complete disappearance of imine and in method II, the
reaction took place within 4 min. After work-up of the reaction
mixture in both methods, N-benzylaniline was obtained in
excellent isolated yield (94 and 96% respectively).
General procedure forthe reductivea of carbonyl compounds
under solvent-free conditions (Method ΙΙ). Carbonyl compound
(1 mmol) and amine (1 mmol) was ground with NaBH4 (1 mmol)
in the presence of cellulose sulfuric acid (0.1 g) under solvent-
free conditions at room temperature. After completion of the
reaction as monitored by TLC, the mixture was washed with
CH2Cl2 (2 × 25 mL) and the combined solvent was dried over
MgSO4.
We then applied these optimal conditions for the reductive
amination of various aldehydes and ketones with aliphatic and
aromatic amines and these transformations were successful and
gave the desired products in good to excellent yields (87 - 98%)
as shown in Table 1.
Evaporation of the solvent and a short-column chromato-
graphy of the product on silica gel (eluent: n-hexane/EtOAc:
18/2) gave the pure product. After work-up all products were
characterized spectroscopically (1H NMR and IR) and showed
physical and spectral data in accordance with their expected
structure by comparison with authentic samples.
As indicated in Table 1, when treated with aniline in the pre-
sence of NaBH4-cellulose sulfuric acid, benzaldehyde func-
tionalized with reducible functional groups such as C=C, CN
and NO2 afforded the corresponding amines without reduction
of the carbon-carbon double bond, CN and NO2 groups (Table 1,
entries 3, 4, 22). Similarly, aliphatic and cyclic ketones under-
went reductive amination successfully to give the corresponding
amines in excellent yields (Table 1, entries 17-21). This method
can be used for anilines with electron-withdrawing groups
which is not possible with [NaBH3CN] and [NaBH(OAC)3],
Results and Discussion
Initially, the condensation of benzaldehyde with aniline
was chosen as the model reaction, to examine the effect of the

One-Pot Reductive Amination of Carbonyl Compounds
Bull. Korean Chem. Soc. 2010, Vol. 31, No. 7 1929
Table 2. Comparison of cellulose sulfuric acid and the other reducing agents in reductive amination of aldehyde and ketones
NaBH4-Cellulose sulfuric acid
Other reducing agent
Carbonyl
Method Ιa
Method ΙΙb
Entry
Amine
Compound
Time
Yieldd
(%)
Time
Yieldd
(%)
Time Yield Time Yield Time Yield
(min)
(min)
(min)
(%)
(min)
(%)
(min)
(%)
1
2
3
4
5
PhCHO
PhCHO
PhCHO
PhNH2
PhCH2NH2
Morpholine
45
2
7
5
28
94
94
93
90
91
4
2
2
1
4
96
95
92
92
94
90
20
60
-
94c
93e
83f
-
120
90
10
60
2
92d
93d
94g
97d
95g
-
-
30
-
-
-
0h
-
Cyclohexanone Piperidine
Cyclohexanone PhNH2
45
85e
240
91
aMethod Ι: Reaction was carried out in EtOH. bMethod ΙΙ: Reaction was carried out under solvent-free conditions. cCu(pph3)2BH4․MeOH.34
dZBHNMP (zinc borohydride N-methyl pyrrolidine).20 e2-(Tributylamino)-ethoxyborohydride.36 fZinc-modified cyanotrihydroborate28 gNaBH4-
silica phosphoric acid.19 hNaBH4-H3BO3.13
the most often used reagents for this purpose (Table 1, entry 8
and 12). However, in order to examine a wider range of amines
and to better illustrate the scope and limitation of this method,
we investigated the reaction with both primary and secondary
amines such as benzylamine, piperidine, pyrrolidine and mor-
pholine using PhCHO as a representative aldehyde, and cyclo-
hexanone as a representative ketone (Table 1, entries 13-16,
18-20). Reductive amination of aliphatic aldehyde, such as
butanal with aniline also gives excellent yield of corresponding
amine (Table 1, entry 23).
for the reductive amination of aldehydes or ketones provides a
novel protocol for synthesis of amines. Moreover, easy reaction
work-up, high reaction rates and yields and neutral condition
make this method more useful for this purpose.
Acknowledgments. We are thankful to the Research Council
of University of Mazandaran for the partial support of this work.
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