Reductive amination of aldehydes and ketones in a heterogeneous system in THF and under solvent-free conditions using sodium borohydride-silica phosphoric acid

Article abstract of DOI:10.1007/s00706-007-0733-z

A chemoselective, 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 silica phosphoric acid in THF and under solvent-free conditions at room temperature is described.

Full text of DOI:10.1007/s00706-007-0733-z

Monatshefte f u¨ r Chemie 139, 21–25 (2008)
DOI 10.1007/s00706-007-0733-z
Printed in The Netherlands
Reductive Amination of Aldehydes and Ketones in a Heterogeneous
System in THF and under Solvent-Free Conditions Using Sodium
Borohydride-Silica Phosphoric Acid
ꢀ
Heshmatollah Alinezhad , Mahmoud Tajbakhsh, and Roja Enayati Ahangar
Department of Chemistry, Mazandaran University, Babolsar, Iran
Received April 25, 2007; accepted May 27, 2007; published online October 31, 2007
#
Springer-Verlag 2007
Summary. A chemoselective, fast, efficient, and high yield-
ing method for the preparation of amines by reductive amina-
tion of aldehydes and ketones using sodium borohydride in the
presence of silica phosphoric acid in THF and under solvent-
free conditions at room temperature is described.
and C–C multiple bonds. For reductive amination, a
variety of reducing agents, such as NaBH CN [4],
3
NaBH(OAc) [5], borane-pyridine [6], tetrahydrobo-
3
rate exchange resin [7], Zn(BH ) [8], Zn(BH ) –
4 2
4 2
ZnCl [9], Zn(BH ) –SiO [10], Ti(O-iPr) –NaBH
4
2
4 2
2
4
Keywords. Silica phosphoric acid; Reductive amination;
Aldehydes; Ketones; NaBH4.
[
wave [13], PhSiH –Bu SnCl [14], Bu SnH [15],
11], decaborane [12], NaBH4 wet clay-micro-
3
2
2
3
Bu SnH–SiO [16], Zr(BH ) Cl (dabco) [17], pico-
3
2
4 2
2
2
lineborane [18], Hantzsch dihydropyridine [19],
NaBH in micellar media [20], and solid acid-acti-
Introduction
4
vated NaBH under solvent-free conditions [21] have
4
Reductive amination of aldehydes and ketones is
one of the most useful methods to prepare amines
in biological and chemical systems [1]. Amines are
very important industrial organic compounds that
have found wide-spread applications as solvents, in-
termediates for pharmaceuticals, raw materials for
resins, textile additives, disinfectants, rubber stabiliz-
ers, corrosion inhibitors, and in the manufacture of
detergents and plastics [2]. The reaction involves the
initial formation of an intermediate carbinol amine,
which dehydrates to form an imine under the reac-
tion conditions. The imine is then protonated to form
an iminium ion. Subsequent reduction of this imi-
nium ion produces the alkylated amine [3]. Catalytic
hydrogenation is an effective method for this conver-
sion that has limited uses with compounds contain-
ing reducible functional groups, such as nitro, cyano,
been developed. However, most of these reagents
may have one or another drawback. For example,
the use of expensive and highly toxic NaBH CN that
3
carries the risk of having residual cyanide in the
products as well as in the work-up stream makes
this procedure less attractive. Clearly the use of
NaBH CN is not acceptable in the context of green
3
synthesis, especially in industry [22]. Tin hydride
reagents are also highly toxic [23].
Recently, we reported reductive amination of
aldehydes and ketones with N-methylpiperidine zinc
borohydride [19] and NaBH [24] in a micellar me-
4
dia. Sodium borohydride is a cheap, safe to handle,
and environmentally friendly reducing agent which
rapidly reduces aldehydes, ketones, and acid chlo-
rides [25]. This reagent is commonly employed in
hydroxylic solvents, such as methanol, ethanol, and
2-propanol, although it is unstable in both methanol
and ethanol due to solvolysis [26].
ꢀ Corresponding author. E-mail: heshmat@umz.ac.ir

2
2
H. Alinezhad et al.
Scheme 1
Acids are widely used as catalysts in industry,
8
od II). 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 silica phos-
phoric acid at room temperature. In method I after
15 min, TLC showed complete disappearance of im-
ine and in method II the reaction took place within
2 min. After work-up of the reaction mixture, N-ben-
zylaniline was obtained in excellent isolated yield
(93 and 95%). We then applied these optimal con-
ditions for the reductive amination of various al-
dehydes and ketones with aliphatic and aromatic
amines and these transformations were successful
and gave the desired products in good to excellent
yields (85–95%) as shown in Table 1.
We also examined chemoselective reductive ami-
nation of functionalized benzaldehydes bearing other
reducible functional groups employing the same
methodologies. As shown in Table 1, aromatic al-
dehydes having nitro and cyano groups underwent
reductive amination to give the corresponding N-
phenylamines in good yields without reduction of
any other functional groups (entries 4 and 6). In
the case of ꢀ,ꢁ-unsaturated aldehydes, such as cin-
namaldehyde, reductive amination was successfully
achieved in excellent yield without reduction of the
carbon-carbon double bond (entry 24). Similarly, al-
iphatic and cyclic ketones underwent reductive ami-
nation successfully to give the corresponding amines
in excellent yields (entries 15 and 22). Weakly acidic
anilines like nitro- and chloroanilines do not usually
undergo clean reductive amination reactions. The most
producing more than 1ꢁ10 Mt=year of products.
The most commonly used acids are HF, H SO ,
2
4
HClO , and H PO (in liquid form or supported on
4
4
3
kieselguhr). Solid acids have many advantages such
as simplicity in handling, decreased reactor and plant
corrosion problems, and environmentally safe dis-
posal. There is much current research and general
interest in heterogeneous systems because of the im-
portance of such systems in industry and in develop-
ing technologies. Silica phosphoric acid is prepared
via reaction of silica chloride and phosphoric acid.
The application of silica phosphoric acid as a stable
and efficient heterogeneous catalyst in organic syn-
thesis has been widely studied [27]. On the other
hand, solvent-free reactions are not only of interest
from an ecological point of view, but in many cases
offer considerable synthetic advantages in terms of
yield, selectivity, and simplicity of the reaction pro-
cedure [26] (Scheme 1).
We report here a method for the efficient reductive
amination of a series of aldehydes and ketones using
NaBH in the presence of silica phosphoric acid.
4
This reaction is of significance because of its versa-
tility and wide application in industry. Silica phos-
phoric acid is a cheap and readily available solid
acid which enables the synthesis of a series of amines
with unprecedented reaction time and yields.
Results and Discussion
We initially examined the reductive anilation of
benzaldehyde with sodium borohydride in the pres-
ence of silica phosphoric acid in THF as the solvent
widely used reagent for this purpose, NaBH CN, is
3
an inefficient and sluggish reagent for the trans-
formation. Both 4-nitro- and 4-chloroaniline react
(
method I) and under solvent-free conditions (meth-

Reductive Amination of Aldehydes and Ketones
23
a
Table 1. Reductive amination of aldehydes and ketones using NaBH –silica phosphoric acid
4
b
c
d
Entry
Carbonyl compound
Amine
Product
Method I
Method II
Ref.
Time= Yield= Time= Yield=
min
%
min
%
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
Ph–CHO
Ph–NH2
Ph–NH2
Ph–NH2
Ph–NH2
Ph–NH2
Ph–NH2
Ph–CH NH–Ph
2
10
22
25
30
16
28
25
20
19
12
13
5
93
90
87
90
90
94
85
85
94
92
90
90
92
94
94
94
90
95
90
92
94
90
88
90
81
4
19
22
25
10
18
15
15
12
8
6
2
2
8
5
2
5
1
95
90
88
86
90
90
[28]
[13]
[41]
[29]
[13]
[29]
[36]
[13]
[30]
[31]
[32]
[28]
[33]
[28]
[34]
[42]
[38]
[28]
[28]
[28]
[33]
[35]
[32]
[29]
[21]
4-Cl–Ph–CHO
2-Cl–Ph–CHO
4-CN–Ph–CHO
4-OMe–Ph–CHO
4-Cl–Ph–CH NH–Ph
2
2-Cl–Ph–CH NH–Ph
2
4-CN–Ph–CH NH–Ph
2
4-OMe–Ph–CH NH–Ph
2
4-NO –Ph–CHO
2
4-NO –Ph–CH NH–Ph
2
2
f
Ph–CHO
Ph–CHO
Ph–CHO
Ph–CHO
Ph–CHO
4-Cl–Ph–NH2
4-OMe–Ph–NH2
4-NO –Ph–NH
Ph–CH NH–Ph–Cl
2
85
85
92
92
90
92
90
93
92
93
94
95
92
92
92
92
88
87
89
Ph–CH NH–Ph–OMe
2
Ph–CH NH–Ph–NO
2
2
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
Ph–NHMe
Ph–CH N(Me)–Ph
2
CH ¼CHCH NH
Ph–NHCH CH¼CH
2
2
2
2
2
Ph–CHO
Ph–CHO
Piperidine
Pyrrolidine
Morpholine
Ph–NH2
Ph–CH –N-pip
2
Ph–CH –N-pyr
2
4
Ph–CHO
CH –(CH ) –CO–CH
Ph–CH –N-morph
2
10
13
12
10
2
10
2
2
15
5
5
31
CH –(CH ) –C(Me)HNH–Ph
2 4
3
2 4
3
3
3
3
CH –(CH ) –CO–CH
3
Pyrrolidine
Piperidine
Ph–NH2
CH –(CH ) –C(Me)H–N–pyr
3
2 4
2 4
CH –(CH ) –CO–CH
3
CH –(CH ) –C(Me)H–N–pip
2 4
2 4
3
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
CH CH CH CHO
Ph–HN–cyclohex
CH ¼CHCH NH cyclohex–NH–CH –CH–CH
7
1
2
8
2
2
22
2
2
2
2
2
Piperidine
Pyrrolidine
Morpholine
Ph–NH2
cyclohex–N–pip
cyclohex–N–pyr
cyclohex–N–morph
CH CH CH CH –NH–Ph
3
2
2
3
2
2
2
Ph–CH¼CHCHO
p–CH O–CO–Ph–CHO
Ph–NH2
Ph–NH2
Ph–CH¼CHCH NH–Ph
2
p–CH O–CO–Ph–CH NH–Ph
3
3
2
a
All reactions were carried out at room temperature and molar ratio of reagent=carbonyl compound=amine was 1=1=1 and 0.2 g,
.5 mmol silica phosphoric acid were used
1
All products were characterized spectroscopically ( H NMR and IR) and showed physical and spectral data in accordance with
0
b
their expected structure by comparison with authentic samples
c
Method I: Reaction was carried out in THF
Method II: Reaction was carried out under solvent-free condition
Yields refer to pure isolated products
4-Chloroaniline under similar reaction conditions with 1 mmol excess of NaBH afforded 85% of N-benzyl-4-chloroaniline
4
within 15 min (entry 7)
d
e
f
efficiently with benzaldehyde within 12–25 min (en-
tries 7 and 9). However, in order to examine a wider
range of amines to better illustrate the scope and
limitation of these methods, we investigated the re-
action with both primary and secondary amines,
such as allyl amine, piperidine, pyrrolidine, and mor-
pholine using PhCHO as a representative aldehyde,
and cyclohexanone and 2-heptanone as representa-
tive ketones (entries 10–22). Reductive amination
of aliphatic aldehyde, such as butanal with aniline
also gives excellent yield of the corresponding amine
with those reported in the literature in Table 2: As
shown in this table reductive amination employing
NaBH and silica phosphoric acid is as good as or
better than comparable reported results. However, in
many cases our results were superior to others. For
example, we compared the reductive amination of
4
cyclohexanone with morpholine using NaBH CN
3
and NaBH(OAc) vs. NaBH –silica phosphoric acid
3
4
(Table 2, entry 6). The reaction with NaBH CN in
3
methanol and in the absence of AcOH was only 34%
complete after 23 h with the formation of about 10%
of the corresponding enamine. The conversion im-
proved to 50% in 23 h with AcOH (1 equiv) with no
enamine formation. The reaction using NaBH(OAc)3
(entry 23).
In order to show the drawbacks and advantages of
our method we have compared some of our results

2
4
H. Alinezhad et al.
Table 2. Comparison of silica phosphoric acid and the other reducing agents in reductive amination of aldehydes and ketones
Entry
Carbonyl compound
Amine
NaBH –silica phosphoric acid
4
Other reducing agents
a
b
a
b
Method I
Method II
Method I
Method II
Time= Yield= Time=
min
Yield= Time= Yield= Time= Yield=
%
min
%
%
min
%
min
c
d
1
2
3
4
5
6
7
8
Ph–CHO
Ph–CHO
Ph–CHO
Ph–NH2
4-NO –Ph–NH
10
19
10
13
2
15
15
13
93
94
94
90
95
90
90
94
4
12
8
6
1
8
8
5
95
92
93
90
95
92
92
92
15
90
60
50
60
23
180
110
92
85
83
15
40
30
15
10
20
–
94
86
e
g
f
f
2
2
d
Morpholine
CH ¼CHCH NH
99
94
f
Ph–CHO
92
42
34
2
2
2
i
j
d
Cyclohexanone
Cyclohexanone
Cyclohexanone
CH –(CH ) –CO–CH
3
Ph–NH
93
35
–
2
h
d
Morpholine
Morpholine
Ph–NH2
e
96
92
h
f
25
92
3
2 4
a
Method I: Reaction was carried out in solvent
Method II: Reaction was carried out under solvent-free condition
NaBH –PTSA (p-toluenesulfonic acid monohydrate) [35]
4
b
c
d
e
f
NaBH –H BO (in entry 3, benzyl alcohol and in entry 6, cyclohexanol were obtained as a major product) [35]
4
3
3
Na[BH(OAc) ] [30]
3
N-Methylpiperidine zinc borohydride (ZBNMPP) [24]
Zinc-modified cyanotrihydroborate [37]
[Zr(BH ) Cl (dabco) ](ZrBDC) [17]
4 2 2 2
Tetrahydroborate exchange resin [39]
g
h
i
j
Na[BH CN] [40, 38]
3
completed in 3 h. This reaction with NaBH –silica
4
handling techniques is the notable advantage of this
method. Moreover, easy reaction work-up, high re-
action rates and yields, and neutral condition make
this method a useful addition to the category of pro-
cedures used for the reductive preparation of amines.
Furthermore, due to compatibility of this reagent
system with a variety of otherwise reducible func-
tional groups, this method can provide an easy ac-
cess to analogous amines bearing functionalized
pendant chains.
phosphoric acid whether in THF or under solvent-
free conditions completed after 8–15 min.
In another comparison the reductive amination of
benzaldehyde with morpholine, in the reaction with
NaBH –H BO under solvent-free conditions, ben-
4
3
3
zyl alcohol was obtained in 99% yield after 30 min
as a major product. While in our method, using
NaBH –silica phosphoric acid, corresponding alco-
4
hol was not obtained, and reaction completed in 8–
1
0 min with the high yield of N-benzylmorpholine
Table 2, entry 3). Similarly, the reaction of cyclo-
(
Experimental
hexanone with morpholine led to only 35% N-cyclo-
hexylmorpholine and cyclohexanol formed as major
product (Table 2, entry 6). This reaction with silica
phosphoric acid took only 8–15 min and gave a high
yield of the corresponding amine (Table 2, entry 6).
Materials were purchased from Fluka and Merck companies.
The reactions were monitored by TLC using silica gel plates
and the products were purified by flash column chromatogra-
phy on silica gel (Merck, 230–400 mesh) and were identified
by comparison of their spectra ( H NMR and FTIR) and
1
physical data with those of the authentic samples. H NMR
1
spectra were measured at 270 and 300 MHz on a JEOL spec-
trometer with tetramethylsilane (TMS) as the internal refer-
Conclusion
We have established a direct reductive amination of
aldehydes and ketones using sodium borohydride
activated by silica phosphoric acid in THF and sol-
vent-free conditions. Solvent-free conditions can of-
fer a great opportunity for green chemistry. The use
of inexpensive reducing agent requiring no special
ence and CDCl as the solvent. IR spectra were recorded on a
3
Pye-unicam SP 1100 spectrophotometer. Elemental analysis
was performed with a CHN-600 Elemental Analyzer for mac-
ro samples, system 785-500, 1988 LECO Corporation; results
agreed within standard errors with calculated values. Silica
phosphoric acid was prepared according to the reported pro-
cedure [27].

Reductive Amination of Aldehydes and Ketones
25
General Procedure for the Reductive Amination
of Carbonyl Compounds in THF (Method I)
Carbonyl compound (1mmol) and 1 mmol amine were mixed
[10] Ranu BC, Majee A, Sakar A (1998) J Org Chem 63: 370
[
11] a) Miriyala B, Bhattacharyya S, Williamson JS ( 2004)
Tetrahedron 60: 1463; b) Kumpaty HJ, Williamson JS,
Bhattacharyya S (2003) Synth Commun 33: 1411; c)
Neidigh KA, Avery MA, Williamson JS, Bhattacharyya
SI (1998) J Chem Soc Perkin Trans 2527; d)
Bhattacharyya S (1995) J Org Chem 60: 4928; e)
Bhattacharyya S, Chatterjee A, Williamson JS
3
in 5 cm THF and then treated with 1 mmol NaBH and the
4
pH was adjusted to neutral by addition of 0.2 g silica phos-
þ
phoric acid (0.5mmol H ). 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
3
(1995) Synlett: 1079
12] Base JW, Lee SH, Cho YJ, Yoon CM (2000) J Chem Soc
Perkin Trans 1: 145
with 2ꢁ15 cm CH Cl or ether. The solvent was evaporated
2
2
[
and a pure product was obtained. If necessary, the crude prod-
uct was purified by column chromatography on silica gel
[
[
[
[
[
13] Varma RS, DAahiya R (1998) Tetrahedron 54: 6293
14] Apodaca R, Xiao W (2001) Org Lett 3: 1754
15] SuwaT,SugiyamaE,ShibataI,BabaA(2000)Synlett:556
16] Hiror R, MiyoShi N, Wada M (2002) Chem Lett: 274
17] Firouzabadi H, Iranpoor N, Alinezhad H (2003) Bull
Chem Soc Jpn 76: 143
(
eluent: n-hexane=EtOAc¼ 20=1).
General Procedure for the Reductive Amination of Carbonyl
Compounds Under Solvent Free Condition (Method II)
Carbonyl compound (1mmol) and 1 mmol amine was ground
with 1 mmol NaBH in the presence of 0.2 g silica phosphoric
4
acid (0.5mmol H ) under solvent-free condition at room
temperature. After complete transformation of the aldehyde
or ketone as monitored by TLC, the mixture was washed with
3
3
vents were dried (Na SO ). Evaporation of the solvent and a
short-column chromatography of the product on silica gel
(
[
[
[
18] Sato S, Sakamoto T, Miyazawa E, Kikugawa Y (2004)
Tetrahedron 60: 7899
19] TakaShi I, Kazuhiro N, Michiko M, Hyroyuki I, Akio
(2004) Tetrahedron 60: 6649
20] Alinezhad H, Tajbakhsh M, Salehian F (2005) Monatsh
Chem 136: 2029
þ
ꢁ25 cm CH Cl or ether and the combined washing sol-
2
2
2
4
[
[
21] Cho BT, Kang SK (2005) Tetrahedron Lett 61: 5725
22] Sato S, Sakamoto T, Miyazawa E, Kikugawa Y (2004)
Tetrahedron 60: 7899
eluent: n-hexane=EtOAc¼ 20=1) gave the pure product.
After work-up all products were characterized spectroscopi-
1
cally ( H NMR and IR) and showed physical and spectral data
in accordance with their expected structure and by comparison
with authentic samples. Yield refers to pure isolated products.
[23] Pereyre M, Quintard JP, Rahm A (1987) Tin in organic
Synthesis. Butterworths, London, p 6
[
[
24] AlinezhadH,TajbakhshM,ZamaniR(2006)Synlett:431
25] Paquatte LL (ed) (1995) Reagent for Organic Synthesis,
Vol. 7. Wiley, New York, NY, p 4522
Acknowledgements
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Phosphorus Sulfur Silicon 179: 2177
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Chem 50: 1927
Financial support of this work from the Research Council of
Mazandaran University is gratefully acknowledged.
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