Eco-friendly synthesis of imines by ultrasound irradiation

Article abstract of DOI:10.1016/j.tetlet.2007.01.014

A series of imines was synthesized by an ultrasound-assisted reaction of aldehydes and primary amines using silica as the promoter. Products were obtained in high yields even in large scale synthesis.

Full text of DOI:10.1016/j.tetlet.2007.01.014

Tetrahedron Letters 48 (2007) 1845–1848
Eco-friendly synthesis of imines by ultrasound irradiation
b
b
a
c
´
Karla P. Guzen, Alexandre S. Guarezemini, Aline T. G. Orfao, Rodrigo Cella,
˜
a
a,b,c,
*
´
Claudio M. P. Pereira and Helio A. Stefani
a
ˆ
ˆ
Faculdade de Ciencias Farmaceuticas, Universidade de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil
bDepartamento de Biofı´sica, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil
cInstituto de Quı´mica, Universidade de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil
Received 16 October 2006; revised 15 December 2006; accepted 3 January 2007
Available online 7 January 2007
Abstract—A series of imines was synthesized by an ultrasound-assisted reaction of aldehydes and primary amines using silica as the
promoter. Products were obtained in high yields even in large scale synthesis.
Ó 2007 Elsevier Ltd. All rights reserved.
The nitrogen atom is present in most natural products,
biologically important molecules, pharmaceuticals, and
dyes.1 Imines and their derivatives are useful intermedi-
ates in organic synthesis,2 in particular for the prepara-
tion of heterocycles and non-natural b-aminoacids.3
in terms of energy conservation and waste minimiza-
tion.12 Recently we have developed general methods
for the synthesis of numerous useful organic compounds
under ultrasound irradiation, for example, aryl acetyl-
enes13 and heterocycles.14 Moreover, we have used son-
ochemistry to accelerate Suzuki–Miyaura reactions.15
Several methods for the synthesis of imines are described
in the literature; they can be obtained from aldehydes,4
gem-dibromomethylaryl derivates,5 formamides,6 palla-
dium catalyzed amination7 as well as by polymer-sup-
ported.8 However, these methodologies often require
complex procedures, long reaction times, and large
quantities of aromatic solvents. This conventional phase
solution chemistry typically involves distillation under
reduced pressure or azeotropic removal of water by a
Dean–Stark apparatus. Solvent-free synthesis of imines
and enamines under microwave irradiation has been de-
scribed.9 However, this method was applied for a limited
number of compounds and the possibility of scaling up
the synthesis was not evaluated. More recently, Chak-
raborti et al. reported the synthesis of imines using mag-
nesium perchlorate as the catalyst with reaction times
ranging from 15 to 480 min.10
As a part of our growing interest in sonochemistry, with
the aim of improving the synthesis of imines, we decided
to undertake a systematic study of the preparation of
imines using this alternative energy source (Scheme 1).
First of all, we screened a wide variety of promoter to
the imines synthesis (Table 1) using benzaldehyde (1a)
and p-methoxyaniline (2a) in ethanol under ultrasound
irradiation as a standard reaction. Looking for cleaner
approaches to classical syntheses, we chose some solid
supported catalysts, for example, clay, silica or resin
due to their low impact in the environment, possibilities
to recycle them and in some cases their high availability
from nature. As can be seen in Table 1, the best results
were reached with alumina and silica (Table 1, entries 2
and 6) 83% and >99% yields, respectively. When no pro-
moter (Table 1, entry 1) was used the desired product 3a
(N-benzylidene-4-methoxybenzenamine) was obtained
in a 57% yield. The resins DOWEXÒ and AmberlystÒ
It is well known that many organic reactions are accel-
erated by ultrasound irradiation.11 Compared with tra-
ditional methods, this technique is more convenient
taking green chemistry concepts into account. Sono-
chemistry is considered a processing aid (or auxiliary)
R1
O
N
)))
+
R1NH2
"Promoter"
R
R
1
3
2
*
Corresponding author. Tel.: +11 55 11 818 3654; fax: +11 55 11 3 815
4418; e-mail: hstefani@usp.br
Scheme 1. General systematic study.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.014

1846
K. P. Guzen et al. / Tetrahedron Letters 48 (2007) 1845–1848
Table 3. Synthesis of imines under ultrasound irradiation using silica
Table 1. Choose of promoter
Entry Aldehyde (1)
Amine (2)
Imine Yielda
OMe
O
NH2
(3)
(%)
)))
OMe
O
N
+
"promoter"
EtOH
H
H
1
3a
>99 (96)b
OMe
H2N
1a
3a
2a
1a
1b
2a
Entry
Catalyst
Yielda (%)
O
1
2
3
4
5
6
Absence
Alumina
DOWEXÒ
AmberlystÒ
CeliteÒ
57
83
39
26
73
O
2
3
2a
2a
3b
3c
85
Silica
>99
O
a Isolated yields.
O
>99 (91)b
H
O
1c
(Table 1, entries 3 and 4) were employed also as a pro-
moters, but very low yields were obtained. When CeliteÒ
(Table 1, entry 5) was used the product (3a) was
obtained in a good yield, 73%.
O
H
4
2a
3d
>99
MeO
We also tested the appropriate quantities of silica neces-
sary to perform the synthesis of imines under ultrasound
irradiation (Table 2). These experiments led us to con-
clude that 5 equiv of silica furnishes the respective prod-
uct in a quantitative yield (Table 2, entry 3).
1d
5
6
1a
3e
3f
>99 (90)b
H2N
2b
We also analyzed the effect of the reaction solvent. In
addition to ethanol we tested ethyl acetate, dichloro-
methane and THF (Table 2, entries 4–6). As can be seen
a similar result was obtained when dichloromethane was
used (Table 2, entry 5), but we chose ethanol due to sev-
eral advantages. Among them ethanol is an inexpensive
solvent, derivated from a renewable source and very
much available all over the world.
1c
2b
2b
90
O
H
7
3g
85
1e
O
The scope and generality of this process are illustrated
by a series of 20 imines as can be seen in Table 3. A wide
range of aromatic and heteroaromatic aldehydes were
employed and all imines were obtained in excellent
yields (Table 3, entries 1–16), and was observed that is
a general method that tolerates both electron-withdraw-
ing and electron-donating substituents. An a,b-unsatu-
rated aldehyde (cinnamaldehyde 1h) was also used and
the yields were excellent (Table 3, entries 7, 9, 17 and
19).
O2N
H
8
9
2b
3h
3i
86
88
1f
1e
H2N
2c
10
11
12
13
1f
2c
2c
2c
2c
3j
96 (93)b
87
98
90
1b
1c
1d
3k
3l
The reaction worked very well with 2-ethyl butyralde-
hyde 1h, an aliphatic aldehyde (Table 3, entries 20–23),
but when formaldehyde was used no reaction was
3m
O
H
N
H2N
14
3n
93 (90)b
H
Table 2. Loading of silica
2d
1g
Entry
Silica ratio (equiv)
Solvent
Yielda (%)
15
16
17
1a
1c
1e
2d
2d
2d
3o
3p
3q
86
90
88
1
2
3
4
5
6
1
2.5
5
5
5
EtOH
EtOH
EtOH
AcOEt
Dichloromethane
THF
87
93
>99
60
98
75
H2N
5
18
1a
3r
95
a Isolated yields.
2e

K. P. Guzen et al. / Tetrahedron Letters 48 (2007) 1845–1848
1847
Table 3 (continued)
and third utilization and in the fifth the yield decayed by
half.
Entry
Aldehyde (1)
Amine (2)
Imine
(3)
Yielda
(%)
In conclusion, we have developed a mild, convenient
and improved protocol for the preparation of imines
by ultrasound irradiation. Among the advantages of
the method we can mention: (i) the reaction is simple
to execute; (ii) the yields are excellent (85–>99%); (iii)
a very simple work-up; and (iv) short reaction time
(10 min).
19
1e
2e
3s
96 (90)b
O
H
20
2a
3t
88
1h
21
22
23
1h
1h
1h
2b
2c
2d
3u
3v
99
94
95
Moreover, this protocol can be included in some green
chemistry concepts as (i) atom economic; (ii) waste
minimization; and (iii) energy conservation.
3w
O
24
25
2a
2a
3x
3y
nr
nr
1i
Acknowledgments
O
The authors wish to thank FAPESP (Grant 03/01751-8
and the Scholarship 03/13475-5-CMPP, 03-13897-7-
RC), and CNPq agencies for financial support.
1j
O
26
2a
3z
nr
H
H
Supplementary data
1k
a Isolated yields.
b Scale-up of 50 mmol.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2007.01.014.
observed (Table 3, entry 26). Ketones were tested (Table
3, entries 24 and 25), but no reaction was observed too.
References and notes
About primary amines 2, we used aromatic amines as
well as benzylic and aliphatic amines and as can be seen
in Table 3 no difference in the reactivity was observed.
All imines were obtained in a very high yield and in
some cases quantitatives yields were reached.
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100
80
60
40
20
0
1
2
3
4
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Number of cycles
Figure 1. Reusability of the promoter.

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